Cycloalkylmethylamines

ABSTRACT

The present invention provides novel cycloalkylmethylamine derivatives, and methods of preparing cycloalkylmethylamine derivatives. The present invention also provides methods of using cycloalkylmethylamine derivatives and compositions of cycloalkylmethylamine derivatives. The pharmaceutical compositions of the compounds of the present invention can be advantageously used for treating and/or preventing obesity and obesity related co-morbid indications and depression and depression related co-morbid indications.

This application is a continuation application of U.S. application Ser.No. 13/175,824, filed Jul. 1, 2011; which claims priority to ProvisionalApplication No. 61/361,108, filed Jul. 2, 2010. This application is alsoa continuation-in-part of U.S. application Ser. No. 13/866,905, filedApr. 19, 2013; which is a continuation application of U.S. applicationSer. No. 13/176,526, filed Jul. 5, 2011, now U.S. Pat. No. 8,445,714;which is a divisional application of U.S. application Ser. No.11/856,670, filed Sep. 17, 2007, now U.S. Pat. No. 7,989,500; whichclaims the benefit of U.S. Provisional Application No. 60/825,868, filedSep. 15, 2006. The above-identified applications are incorporated hereinby reference in their entireties.

TECHNICAL FIELD

The present invention relates to cycloalkylmethylamine derivatives,synthesis of cycloalkylmethylamine derivatives and methods of usingcycloalkylmethylamine derivatives for the pharmacological treatment ofobesity and obesity related co-morbid indications.

BACKGROUND

Obesity is a chronic disease that affects millions of people across theworld especially in the developed countries. It is defined by excessbody fat and is generally measured by calculating a person's BMI (bodymass index). If a person's BMI is 30 or above, he or she considered tobe obese. Obesity can cause a number of health problems either directlyor indirectly, such as, for example, type 2 diabetes, coronary heartdisease, high blood triglycerides, high blood pressure and stroke.Obesity also raises risk of certain types of cancer. Obese men are morelikely than normal-weight peers to die from cancer of the colon, rectum,and prostate. Obese women are more likely than non-obese women to diefrom cancer of the gallbladder, breast, uterus, cervix and ovaries.Death from some cancers may be more likely because obesity makes thecancers harder to detect in the early stages (for example, the initialsmall lump of breast cancer may not be felt in an obese woman). Recentstudies show obesity increases the risk of Alzheimer's-type dementia.Other disease and health problems linked to obesity include: gallbladderdisease, gallstones, osteoarthritis, gout or joint pain, sleep apnea,psychological and social problems.

Obesity is caused by multiple factors, the primary factor being geneticswhich is the one factor relating to obesity over which individuals haveno control. Other important factors involved in obesity are: themechanisms of fat storage; the balance between energy intake and energyexpenditure; an individual's life style: eating habits and exercise; andpsychological, cultural and socioeconomic influences. Despite theseeming inexorable progression of this disease, there have been limitedadvances in the pharmacotherapy of this condition. Drugs to treatobesity can be divided into three groups: those that reduce food intakeor appetite suppressants; those that alter metabolism or block theabsorption of fat; and those that increase thermogenesis. Currently,there are only two drugs approved by the FDA for the long-term treatmentof obesity and they are fat absorption blocker orlistat (XENICAL®) andthe appetite suppressant sibutramine (MERIDIA®). The only thermogenicdrug combination that has been tested is ephedrine and caffeine, butthis treatment has not been approved by regulatory agencies.

The fat absorption blocker, orlistat works in the gastrointestinal tractby blocking an enzyme that is needed to digest fat. Instead of beingabsorbed from the intestine, up to one-third of the fat that a personconsumes is excreted in the stool. In addition, orlistat blocks theabsorption of needed fat-soluble vitamins A, D, E, and K, as well asbeta-carotene. This is one of the major limitations of this drug for thelong term use in the treatment of obesity. Most commonly reported otherside effects of orlistat are bloating, diarrhea and oily stools.

In the appetite suppressant category, a few noradrenergic andserotonergic drugs belong to a family of 2-arylethylamines are currentlyavailable in the market for the treatment of obesity. The noradrenergicagents such as phenylpropanolamine, (ACUTRIM®, DEXATRIM®),diethylpropion (TENUATE®), and phentermine (FASTIN®, IONAMIN®) areapproved for the short-term treatment of obesity. Whereas, noradrenergicand serotonergic agent sibutramine (MERIDIA®) is the only drug currentlyapproved for the long-term treatment of obesity in the appetitesuppressant category. Sibutramine has cyclobutanemethylamine backboneand it is this backbone mainly responsible for its uniquepharmacological properties.

In the last 10 years, a number of reports have been published on thepossible use of sibutramine, either alone or in combination with othertherapeutic agents, for the treatment and/or prevention of a varietydiseases and/or disorders in addition to obesity (see, Montana, J. G.International Application Publication No. WO 2004/058237; Lulla, A. etal., International Application Publication No. WO 2004/096202; Jerussi,T. P. et al., International Application Publication No. WO 02/060424;Senanayake, C. H. et al., International Application Publication No. WO01/51453; Heal, D. J. International Application Publication No. WO01/00205; Birch, A. M. et al., International Application Publication No.WO 01/00187; Mueller, P. International Application Publication No. WO00/32178; Bailey, C. International Application Publication No. WO98/11884; Kelly, P. International Application Publication No. WO98/13034). For examples: treatment of nausea, emesis, and relatedconditions; cognitive dysfunctions; eating disorders; weight gain;irritable bowel syndrome; obsessive compulsive disorders; plateletadhesion; apnea, affective disorders such as attention deficitdisorders, depression, and anxiety; male and female sexual functiondisorders; restless leg syndrome; osteoarthritis; substance abuseincluding nicotine and cocaine addiction; narcolepsy; pain such asneuropathic pain, diabetic neuropathy, and chronic pain; migraines;cerebral function disorders; chronic disorders such as premenstrualsyndrome; and incontinence.

In general, sibutramine has a number of therapeutic benefits because ofits unique pharmacological properties. However, sibutramine'stherapeutic use for the treatment of obesity, and other diseases anddisorders is currently not fully utilized because of certain limitationsand adverse side effects associated with the drug. The major adverseevents reported, in some cases life threatening, include increase inblood pressure and the side effects derived from the drug-druginteractions, for example, serotonin syndrome. The majority of theseadverse events are, to some extent, metabolism-based. Sibutramine exertsits pharmacological actions predominantly via its secondary (M₁) andprimary (M₂) amine metabolites. Sibutramine is metabolized in the liverprincipally by the cytochrome P450 (3A4) isozymes, to desmethylmetabolites, M₁ and M₂. These active metabolites are further metabolizedby hydroxylation and conjugation to pharmacologically inactivemetabolites, M₅ and M₆. The elimination half-lives of therapeuticallyactive primary and secondary metabolites M₁ and M₂ are 14 and 16 hours,respectively. It is evident from a number literature reports thatcytochrome P450 mediated metabolism and the long half lives of activemetabolites (M₁ and M₂) are to a great extent responsible for adverseevents such as increased blood pressure and other side effects derivedfrom drug-drug interactions of sibutramine.

Therefore, there is a need and great demand for safer and effective nextgeneration appetite suppressants for the treatment of obesity. An idealdrug in this class should have potent appetite suppressant activity, aproven effect on fat loss, be well tolerated during acute and chronicadministration and have alleviated side effects when compared tosibutramine and phentermine.

SUMMARY

The present invention is directed towards compositions of novelcycloalkylmethylamine derivatives and the use of the compositions forthe treatment of obesity and related co-morbid conditions and depressionand related co-morbid conditions.

The present invention provides methods for synthesizing suchcycloalkylmethylamine derivatives. The present invention also providesmethods for using cycloalkylmethylamine derivatives and pharmaceuticalcomposition of cycloalkylmethylamine derivatives for treating orpreventing obesity and co-morbid diseases and/or disorders and fortreating or preventing depression and co-morbid diseases and/ordisorders.

The compounds of the present disclosure are advantageous because oftheir favorable metabolic, pharmacokinetics and pharmacologicalprofiles.

In various aspects, the present disclosure providescycloalkylmethylamine derivatives of structural Formulae (I) or (II):

or isomer or pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, 4, or 5;

SP is a spacer, wherein the spacer is C₁₋₆ alkylene, and wherein one ormore of the carbons of the C₁₋₆ alkylene can optionally be replaced withO, S, or NR⁶, wherein R⁶ can be H or C₁₋₆ alkyl;

X is O, S, NH, CH₂, or alkylene;

Z is O, S, NH, CH₂, or a direct bond;

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, C₁₋₆ alkyl,aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl,heteroarylalkyl, acylalkyloxycarbonyl, acyloxyalkyloxycarbonyl,acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, C₁₋₆ alkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonyllalkylamino,alkylasulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino,arylalkylamino, dialkkylamino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, arylloxycarbonylalkoxy,aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate,sulfate, sulfonate, or sulfonamide; optionally R¹, R², R³, R⁴, and R⁵can be substituted with the isotopes ²H (deuterium), 3H (tritium), 13C,36Cl, 18F, 15N, 17O, 18O, 31P, 32P, and 35S; and

“*” denotes a carbon capable of being optically active.

The compounds of the present disclosure include R isomers, S isomers,and mixtures of R and S isomers.

In certain aspects, the present disclosure providescycloalkylmethylamine derivatives of structural Formulae (III), (IV),(V), (VI), (VII), (VIII), or (IX):

or isomer or pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, 4, or 5;

SP is a spacer, wherein the spacer is C₁₋₆ alkylene, and wherein one ormore of the carbons of the C₁₋₆ alkylene can optionally be replaced withO, S, or NR⁶, wherein R⁶ can be H or C₁₋₆ alkyl;

X is O, S, NH, CH₂, or alkylene;

Z is O, S, NH, CH₂, or a direct bond;

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, C₁₋₆ alkyl,aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl,heteroarylalkyl, acylalkyloxycarbonyl, acyloxyalkyloxycarbonyl,acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, C₁₋₆ alkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonyllalkylamino,alkylasulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino,arylalkylamino, dialkkylamino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, arylloxycarbonylalkoxy,aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate,sulfate, sulfonate, or sulfonamide; optionally R¹, R², R³, R⁴, and R⁵can be substituted with the isotopes ²H (deuterium), ³H (tritium), ¹³C,³⁶Cl, ¹⁸F, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, and ³⁵S; and

“*” denotes a carbon capable of being optically active.

The compounds of the present disclosure include R isomers, S isomers,and mixtures of R and S isomers.

In certain aspects, the present disclosure providescycloalkylmethylamine derivatives of structural Formulae (X), (XI),(XII), (XIII), (XIV), (XV), (XVI), or (XVII):

or isomer or pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, 4, or 5;

SP is a spacer, wherein the spacer is C₁₋₆ alkylene, and wherein one ormore of the carbons of the C₁₋₆ alkylene can optionally be replaced withO, S, or NR⁶, wherein R⁶ can be H or C₁₋₆ alkyl;

X is O, S, NH, CH₂, or alkylene;

Z is O, S, NH, CH₂, or a direct bond;

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, C₁₋₆ alkyl,aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl,heteroarylalkyl, acylalkyloxycarbonyl, acyloxyalkyloxycarbonyl,acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, C₁₋₆ alkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonyllalkylamino,alkylasulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino,arylalkylamino, dialkkylamino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, arylloxycarbonylalkoxy,aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate,sulfate, sulfonate, or sulfonamide; optionally R¹, R², R³, R⁴, and R⁵can be substituted with the isotopes ²H (deuterium), ³H (tritium), ¹³C,³⁶Cl, ¹⁸F, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, and ³⁵S; and

“*” denotes a carbon capable of being optically active.

The compounds of the invention include both R and S compounds, andmixture of both R and S compounds.

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of structural Formulae(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),(XII), (XIII), (XIV), (XV), (XVI), or (XVII) and a pharmaceuticallyacceptable carrier, excipient, or diluent.

In various aspects, the present disclosure provides methods of treatingor preventing obesity in a patient, the method comprising administeringto a patient in need of such treatment an effective amount of any one ofthe compounds of structural Formulae (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), or(XVII). In certain aspects, the compound is selected from any one ofstructural Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or(IX). In further aspects, the compound is selected from any one of thecompounds of EXAMPLES 1-87. In further aspects, the method furthercomprises treating an obesity-related co-morbid symptom.

In various aspects, the present disclosure provides methods for treatingor preventing depression in a patient, the method comprisingadministering to a patient in need of such treatment an effective amountof any one of the compounds of structural Formulae (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV),(XV), (XVI), or (XVII). In certain aspects, the compound is selectedfrom any one of structural Formulae (I), (II), (X), (XI), (XII), (XIII),(XIV), (XV), (XVI), or (XVII). In further aspects, the compound isselected from any one of the compounds of EXAMPLES 1-87. In furtheraspects, the method further comprises treating a depression-relatedco-morbid symptom.

DETAILED DESCRIPTION

This invention provides compounds, pharmaceutical compositions andmethods for pharmacological treatment of obesity and related co-morbiddiseases and/or disorders and depression and co-morbid diseases and/ordisorders. This invention also provides methods for synthesis of novelappetite suppressants. However, prior to describing this invention infurther detail, the following terms will be first defined.

DEFINITIONS

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg (1992) “Advanced Organic Chemistry 3^(rd) Ed.” Vols.A and B, Plenum Press, New York. The practice of the present inventionwill employ, unless otherwise indicated, conventional methods of massspectroscopy, protein chemistry, biochemistry, recombinant DNAtechniques and pharmacology, within the skill of the art. Thecompositions and formulations described herein can be practicedemploying the pharmaceutically acceptable excipients and salts availablein Remington's Pharmaceutical Sciences, 18^(th) Edition (Easton, Pa.:Mack Publishing Company, 1990).

“Compounds of the invention” refers to compounds encompassed bystructural Formulae (I) disclosed herein. The compounds of the inventioncan be identified either by their chemical structure and/or chemicalname. When the chemical structure and chemical name conflict, thechemical structures is determinative of the identity of the compound.The compounds of the invention may contain one or more chiral centersand/or double bonds and therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereoisomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds of theinvention may also exist in several tautomeric forms including the enolform, the keto form and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds. The compounds of the invention also includeisotopically labeled compounds where one or more atoms have an atomicmass different from the atomic mass of conventionally found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention include, but are not limited to ²H, ³H, ¹³C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl. Further, it should be understood, whenpartial structures of the compounds of the invention are illustrated,that brackets of dashes indicate the point of attachment of the partialstructure to the rest of the molecule.

“Composition of the invention” refers to at least one compound of theinvention and a pharmaceutically acceptable vehicle, with which thecompound is administered to a patient. When administered to a patient,the compounds of the invention are administered is isolated form, whichmeans separated from a synthetic organic reaction mixture.

Where a substituent can vary in the number of atoms or groups of thesame kind (e.g., alkyl groups can be C₁, C₂, C₃, etc.), the number ofrepeated atoms or groups can be represented by a range (e.g., C₁-C₆alkyl) which includes each and every number in the range and any and allsub ranges. For example, C₁-C₃ alkyl includes C₁, C₂, C₃, C₁₂₉ C₁₋₃, andC₂₋₃ alkyl.

“Alkyl” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), cycloprop-1-en-1yl, cycloprop-2-en-1yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Theterm “C₁₋₆ alkyl” encompasses C₁ alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl, C₅alkyl, C₆ alkyl, and any sub-range thereof.

The term “alkyl” specifically intended to include radicals having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl,” are used. Preferably, an alkyl group comprisesfrom 1-20 carbon atoms, more preferably, from 1 to 10 carbon atoms.

“Alkanyl” refers to a saturated branched, straight-chain or cyclic alkylradical derived by the removal of one hydrogen atom from a single carbonatom of a parent alkane. Typical alkanyl groups include but are notlimited to, methanyl; ethanyl; propanyls such as propan-1-yl,propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such asbutan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicalkyl radical having at least one carbon-carbon double bond derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkene. The group may be in either the cis or trans conformation aboutthe double bond(s). Typical alkenyl groups include, but are not limitedto, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl,cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien 1-yl, etc.; and the like.

“Alkylene” refers to a divalent radical that is a branched or unbranchedhydrocarbon fragment containing the specified number of carbon atoms,and having two points of attachment. Alkylenes are optionallysubstituted with one, two or three substituents. The term “C₁₋₆alkylene” encompasses C₁ alkylene, C₂ alkylene, C₃ alkylene, C₄alkylene, C₅ alkylene, C₆ alkylene, and any sub-range thereof. Examplesof alkylenes include without limitation: methylene (—CH₂—, a C₁alkylene), ethylene (—CH₂CH₂—, a C₂ alkylene), propylene (—CH₂CH₂CH₂—, aC₃ alkylene), and butylene (—CH₂CH₂CH₂CH₂—, a C₄ alkylene).

“Alkynyl” refers to an unsaturated branched, straight-chain or cyclicalkyl radical having at least one carbon-carbon triple bond derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such asbut-1-yn-1-yl, but-1-yn3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Acyloxyalkyloxycarbonyl” refers to a radical —C(O)OR′R″OC(O)R′″, whereR′, R″, and R′″ are each independently hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but not limited to —C(O)OCH₂OC(O)CH₃, —C(O)OCH₂OC(O)CH₂CH₃,—C(O)OCH(CH₃)OC(O)CH₂CH₃, —C(O)OCH(CH₃)OC(O)C₆H₅ and the like.

“Acylalkyloxycarbonyl” refers to a radical —C(O)OR′R″C(O)R′″, where R′,R″, and R′″ are each independently hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but not limited to —C(O)OCH₂C(O)CH₃, —C(O)OCH₂C(O)CH₂CH₃,—C(O)OCH(CH₃)C(O)CH₂CH₃, —C(O)OCH(CH₃)C(O)C₆H₅ and the like.

“Acyloxyalkyloxycarbonylamino” refers to a radical —NRC(O)OR′R″OC(O)R′″,where R, R′, R″, and R′″ are each independently hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but not limited to —NHC(O)OCH₂OC(O)CH₃, —NHC(O)OCH₂OC(O)CH₂CH₃,—NHC(O)OCH(CH₃)OC(O)CH₂CH₃, —NHC(O)OCH(CH₃)OC(O)C₆H₅ and the like.

“Acylalkyloxycarbonylamino” refers to a radical —NRC(O)OR′R″C(O)R′″,where R, R′, R″, and R′″ are each independently hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but not limited to —NHC(O)OCH₂C(O)CH₃, —NHC(O)OCH₂C(O)CH₂CH₃,—NHC(O)OCH(CH₃)C(O)CH₂CH₃, —NHC(O)OCH(CH₃)C(O)C₆H₅ and the like.

“Acylamino” refers to “Amide” as defined herein.

“Alkylamino” means a radical —NHR where R represents an alkyl, orcycloalkyl group as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to, methylamino, ethylamino,1-methylethylamino, cyclohexylamino and the like.

“Alkoxy” refers to a radical —OR where R represents an alkyl, orcycloalkyl group as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to methoxy, ethoxy, propoxy, butoxy,cyclohexyloxy and the like.

“Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy is asdefined herein.

“Alkoxycarbonylalkoxy” refers to a radical —OCR′R″C(O)-alkoxy wherealkoxy is as defined herein. Similarly, where R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to—OCH₂C(O)OCH₃, —OCH₂C(O)OCH₂CH₃, —OCH(CH₃)C(O)OCH₂CH₃,—OCH(C₆H₅)C(O)OCH₂CH₃, —OCH(CH₂C₆H₅)C(O)OCH₂CH₃,—OC(CH₃)(CH₃)C(O)OCH₂CH₃, and the like.

“Alkoxycarbonylalkylamino” refers to a radical —NRCR′R″C(O)-alkoxy wherealkoxy is as defined herein. Similarly, where R, R′, R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to—NHCH₂C(O)OCH₃, —N(CH₃)CH₂C(O)OCH₂CH₃, —NHCH(CH₃)C(O)OCH₂CH₃,—NHCH(C₆H₅)C(O)OCH₂CH₃, —NHCH(CH₂C₆H₅)C(O)OCH₂CH₃,—NHC(CH₃)(CH₃)C(O)OCH₂CH₃, and the like.

“Alkylsulfonyl” refers to a radical —S(O)₂R where R is an alkyl, orcycloalkyl group as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to, methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, and the like.

“Alkylsulfinyl” refers to a radical —S(O)R where R is an alkyl, orcycloalkyl group as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to, methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl, and the like.

“Alkylthio” refers to a radical —SR where R is an alkyl or cycloalkylgroup as defined herein that may be optionally substituted by one ormore substituents as defined herein. Representative examples include,but are not limited to methylthio, ethylthio, propylthio, butylthio, andthe like.

“Amide or Acylamino” refers to a radical —NR′C(O)R″, where R′ and R″ areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to,formylamino acetylamino, cyclohexylcarbonylamino,cyclohexylmethylcarbonyl-amino, benzoylamino, benzylcarbonylamino andthe like.

“Amino” refers to the radical —NH₂

“Aryl” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorine, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleidene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like. Preferable, anaryl group comprises from 6 to 20 carbon atoms, more preferably, between6 to 12 carbon atoms.

“Arylalkyl” refers to an acyclic alkyl in which one of the hydrogenatoms bonded to a carbon atom, typically a terminal or sp³ carbon atom,is replaced with an aryl group. Typically arylalkyl groups include, butnot limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl,naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specificalkyl moieties are intended, the nomenclature arylalkany, arylalkenyland/or arylalkynyl is used. Preferably, an arylalkyl group is(C₆-C₃₀)arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C₁-C₁₀) and the aryl moiety is (C₆-C₂₀), morepreferably, an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g., the alkanyl,alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₈) and the arylmoiety is (C₆-C₁₂).

“Arylalkoxy” refers to an —O-arylalkyl radical where arylalkyl is asdefined herein that may be optionally substituted by one or moresubstituents as defined herein.

“Arylalkoxycarbonylalkoxy” refers to a radical —OCR′R″C(O)-arylalkoxywhere arylalkoxy is as defined herein. Similarly, where R′ and R″ areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to—OCH₂C(O)OCH₂C₆H₅, —OCH(CH₃)C(O)OCH₂C₆H₅, —OCH(C₆H₅)C(O)OCH₂C₆H₅,—OCH(CH₂C₆H₅)C(O)OCH₂C₆H₅, —OC(CH₃)(CH₃)C(O)OCH₂C₆H₅, and the like.

“Arylalkoxycarbonylalkylamino” refers to a radical—NRCR′R″C(O)-arylalkoxy where arylalkoxy is as defined herein.Similarly, where R, R′, R′ and R″ are each independently hydrogen,alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,heteroaryl, heteroarylalkyl, as defined herein that may be optionallysubstituted by one or more substituents as defined herein.Representative examples include, but are not limited to—NHCH₂C(O)OCH₂C₆H₅, —N(CH₃)CH₂C(O)OCH₂C₆H₅, —NHCH(CH₃)C(O)OCH₂C₆H₅,—NHCH(C₆H₅)C(O)OCH₂C₆H₅, —NHCH(CH₂C₆H₅)C(O)OCH₂C₆H₅,—NHC(CH₃)(CH₃)C(O)OCH₂C₆H₅, and the like.

“Aryloxycarbonyl” refers to radical —C(O)—O-aryl where aryl is definedherein that may be optionally substituted by one or more substituents asdefined herein.

“Aryloxycarbonylalkoxy” refers to a radical —OCR′R″C(O)-aryloxy wherearyloxy is as defined herein. Similarly, where R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to—OCH₂C(O)OC₆H₅, —OCH(CH₃)C(O)OC₆H₅, —OCH(C₆H₅)C(O)OC₆H₅,—OCH(CH₂C₆H₅)C(O)OC₆H₅, —OC(CH₃)(CH₃)C(O)OC₆H₅, and the like.

“Aryloxycarbonylalkylamino” refers to a radical —NRCR′R″C(O)-aryloxywhere aryloxy is as defined herein. Similarly, where R, R′, R′ and R″are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl,aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as definedherein that may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to—NHCH₂C(O)OC₆H₅, —N(CH₃)CH₂C(O)OC₆H₅, —NHCH(CH₃)C(O)OC₆H₅,—NHCH(C₆H₅)C(O)OC₆H₅, —NHCH(CH₂C₆H₅)C(O)OC₆H₅, —NHC(CH₃)(CH₃)C(O)OC₆H₅,and the like.

“Carbamoyl” refers to the radical —C(O)NRR where each R group isindependently, hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein.

“Carbamate” refers to a radical —NR′C(O)OR″, where R′ and R″ are eachindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to,methylcarbamate (—NHC(O)OCH₃), ethylcarbamate (—NHC(O)OCH₂CH₃),benzylcarbamate (—NHC(O)OCH₂C₆H₅), and the like.

“Carbonate” refers to a radical —OC(O)OR, where R is alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. Representative examplesinclude, but are not limited to, methyl carbonate (—C(O)OCH₃),cyclohexyl carbonate (—C(O)OC₆H₁₁), phenyl carbonate (—C(O)OC₆H₅),benzyl carbonate (—C(O)OCH₂C₆H₅), and the like.

“Carboxy” means the radical —C(O)OH.

“Cyano” means the radical —CN.

“cycloalkyl” refers to a substituted or unsubstituted cylic alkylradical. Where a specific level of saturation is intended, thenomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typicalcycloalkyl groups include, but are not limited to, groups derived fromcyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In apreferred embodiment, the cycloalkyl group is (C₃-C₁₀) cycloalkyl, morepreferably (C₃-C₇) cycloalkyl.

“Cycloheteroalkyl” refers to a saturated or unsaturated cyclic alkylradical in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Where a specific level of saturation isintended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl”is used. Typical cycloheteroalkyl groups include, but are not limitedto, groups derived from epoxides, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

“Cycloheteroalkoxycarbonyl” refers to a radical —C(O)OR where R iscycloheteroalkyl as defined herein that may be optionally substituted byone or more substituents as defined herein.

“Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl or cycloalkyl group as defined herein that may beoptionally substituted by one or more substituents as defined herein.Representative examples include, but are not limited to dimethylamino,methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, and the like.

“Derived from a drug” refers to a fragment that is structurally relatedto such a drug. The structure of the fragment is identical to the drugexcept where a hydrogen atom attached to a heteroatom (N or O) has beenreplaced with a covalent bond to another group (typically, a promoiety).Note that when a drug is a salt form of a carboxylic, phosphonic orphosphoric acid, the corresponding structural fragment derived from sucha drug is considered to be derived from the protonated acid form.

“Drug” refers to a compound that exhibits therapeutic and/orprophylactic and/or diagnostic utility when administered in effectiveamounts to a patient or a mammal.

“Ester” refers to a radical —C(O)OR, where R is alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl as definedherein that may be optionally substituted by one or more substituents asdefined herein. Representative examples include, but are not limited to,methyl ester (—C(O)OCH₃), cyclohexyl ester (—C(O)OC₆H₁₁), phenyl ester(—C(O)OC₆H₅), benzyl ester (—C(O)OCH₂C₆H₅), and the like.

“Ether” refers to a radical —OR, where R is alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein.

“Halo” means fluoro, chloro, bromo, or iodo.

“Heteroalkoxy” means an —O-heteroalkyl radical where heteroalkyl is asdefined herein that may be optionally substituted by one or moresubstituents as defined herein.

“Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl” refer toalkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which oneor more of the carbon atoms (and any associated hydrogen atoms) are eachindependently replaced with the same or different heteroatomic groups.Typical heteroatomic groups include, but are not limited to —O—, —S—,—O—O—, —S—S—, —OS—, —NR′—, ═N—N═, —N═N—, —N═N—NR′—, —PH—, —P(O)₂—,—O—P(O) —, —S(O—, —S(O)₂—, —SnH₂—, and the like, wherein R′ is hydrogen,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl orsubstituted aryl that may be optionally substituted by one or moresubstituents as defined herein.

“Heteroaryl” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. Preferably, the heteroarylgroup is between 5-20 membered heteroaryl, with 5-10 membered heteroarylbeing particularly preferred. Preferred heteroaryl groups are thosederived from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, oxazole and pyrazine.

“Heteroaryloxycarbonyl” refers to a radical —C(O)OR where R isheteroaryl as defined that may be optionally substituted by one or moresubstituents as defined herein.

“Heteroarylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with a heteroaryl group. Where specific alkylmoieties are intended, the nomenclature heteroarylalkanyl,heteroarylalkenyl and/or heteroarylalkynyl is used. Preferably, theheteroarylalkyl radical is a 6-30 carbon membered heteroarylalkyl, e.g.,the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10membered and the heteroaryl moiety is a 5-20 membered heteroaryl, morepreferably, a 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenylor alkynyl moiety of the heteroarylalkyl is 1-8 membered and theheteroaryl moiety is a 5-12 membered heteroaryl.

“Hydroxy” means the radical —OH.

“Isomer” refers to compounds of the present invention that possessasymmetric carbon atoms (optical centers) or double bonds, theracemates, diastereomers, enantiomers, geometric isomers, structuralisomers and individual isomers are all intended to be encompassed withinthe scope of the present invention.

“Oxo” means the divalent radical ═O.

As used herein, the term “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. The term does not denote a particular ageor gender.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention, which is pharmaceutically acceptable and possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2,2,2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

“Phosphate” refers to a radical —OP(O)(OR′)(OR″), where R′ and R″ areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein.

“Phosphonate” refers to a radical —P(O)(OR′)(OR″), where R′ and R″ areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein.

“Preventing” or “Prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Protecting group” refers to a group of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in Green et al., “ProtectiveGroups in Organic Chemistry”, (Wiley, 2^(nd) ed. 1991) and Harrison etal., “Compendium of Synthetic Organic Methods”, vols. 1-8 (John Wileyand Sons, 1971-1996). Representative amino protecting groups include,but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl,benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl(“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substitutedtrityl groups, allyloxycarbonyl, 9-fluorenylmethyloxy-carbonyl (“FMOC”),nitroveratryloxycarbonyl (“NVOC”) and the like. Representative hydroxylprotecting groups include, but are not limited to, those where thehydroxyl group is either acylated or alkylated such as benzyl, andtrialkylsilyl ethers and allyl ethers.

“Racemate” refers to an equimolar mixture of enantiomers of a chiralmolecule.

“Spacer” refers to a C₁₋₆ alkylene in which one or more of the carbonsof the C₁₋₆ alkylene can optionally be replaced with O, S, or NR⁶,wherein R⁶ can be H or C₁₋₆ alkyl. The C₁₋₆ alkylene is optionallysubstituted. In certain aspects, the C₁₋₆ alkylene is optionallysubstituted by acylalkyloxycarbonyl, acyloxyalkyloxycarbonyl,acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, alkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonyllalkylamino,alkylasulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino,arylalkylamino, dialkkylamino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, arylloxycarbonylalkoxy,aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate,sulfate, sulfonate, or sulfonamide.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituents(s).Typical substituents include, but are not limited to, —X, —R⁵⁴, —O⁻, ═O,—OR⁵⁴, —SR⁵⁴, —S, ═S, —NR⁵⁴R⁵⁵, ═NR⁵⁴, —CX₃, —CF₃, —CN, —OCN, —SCN, —NO,—NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂OR⁵⁴, —OS(O)₂O³¹, —OS(O)₂R⁵⁴,—P(O)(O−)₂, —P(O)(OR¹⁴)(O³¹), —OP(O)(OR⁵⁴)(OR⁵⁵), —C(O)R⁵⁴—C(O)OR⁵⁴,—C(O)NR⁵⁴R⁵⁵, —C(O)O⁻, —C(S)OR⁵⁴, —NR⁵⁶C(O)NR⁵⁴R⁵⁵, —NR⁵⁶C(S)NR⁵⁴R⁵⁵,—NR⁵⁷C(NR⁵⁶)NR⁵⁴R⁵⁵, and —C(NR⁵⁶)NR⁵⁴R⁵⁵, where each X is independentlya halogen; each R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —NR⁵⁸R⁵⁹, —C(O)R⁵⁸ or —S(O)₂R⁵⁸ or optionally R⁵⁸ andR⁵⁹ together with the atom to which they are both attached form acycloheteroalkyl or substituted cycloheteroalkyl ring; and R⁵⁸ and R⁵⁹are independently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl.

“Sulfate” refers to a radical —OS(O)(O)OR, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein.

“Sulfonamide” refers to a radical —S(O)(O)NR′R″, where R′ and R″ areindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined hereinthat may be optionally substituted by one or more substituents asdefined herein or optionally R′ and R″ together with the atom to whichthey are both attached form a cycloheteroalkyl or substitutedcycloheteroalkyl ring. Representative examples include but not limitedto azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,4-(NR′″)-piperazinyl or imidazolyl group wherein said group may beoptionally substituted by one or more substituents as defined herein.R′″ hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein that may beoptionally substituted by one or more substituents as defined herein.

“Sulfonate” refers to a radical —S(O)(O)OR, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein.

“Thio” means the radical —SH.

“Thioether” refers to a radical —SR, where R is alkyl, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein that may be optionally substituted byone or more substituents as defined herein. “Treating” or “Treatment” ofany disease or disorder refers, in one embodiment, to ameliorating thedisease or disorder (i.e., arresting or reducing the development of thedisease or at least one of the clinical symptoms thereof). In anotherembodiment “treating” or “treatment” refers to ameliorating at least onephysical parameter, which may not be discernible by the patient. In yetanother embodiment, “treating” or “treatment” refers to inhibiting thedisease or disorder, either physically (e.g., stabilization of adiscernible symptom), physiologically, (e.g., stabilization of aphysical parameter), or both. In yet another embodiment, “treating” or“treatment” refers to delaying the onset of the disease or disorder.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and is severityand the age, weight, etc., of the patient to be treated, and can bedetermined by one of skill in the art without undue experimentation.

Reference now will be made in detail to preferred embodiments of theinvention. While the invention will be described in conjunction withpreferred embodiments, it will be understood that it is not intended tolimit the invention to those preferred embodiments. To the contrary, itis intended to cover alternatives, modifications, and equivalents as maybe included within the spirit and scope of the invention as defined bythe appended claims.

Compounds of the Invention

The present disclosure provides cycloalkylmethylamine derivatives ofstructural Formulae (I) or (II):

or isomer or pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, 4, or 5;

SP is a spacer, wherein the spacer is C₁₋₆ alkylene, and wherein one ormore of the carbons of the C₁₋₆ alkylene can optionally be replaced withO, S, or NR⁶, wherein R⁶ can be H or C₁₋₆ alkyl;

X is O, S, NH, CH₂, or alkylene;

Z is O, S, NH, CH₂, or a direct bond;

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, C₁₋₆ alkyl,aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl,heteroarylalkyl, acylalkyloxycarbonyl, acyloxyalkyloxycarbonyl,acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, C₁₋₆ alkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonyllalkylamino,alkylasulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino,arylalkylamino, dialkkylamino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, arylloxycarbonylalkoxy,aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate,sulfate, sulfonate, or sulfonamide; optionally R¹, R², R³, R⁴, and R⁵can be substituted with the isotopes ²H (deuterium), 3H (tritium), 13C,36Cl, 18F, 15N, 17O, 18O, 31P, 32P, and 35S; and

“*” denotes a carbon capable of being optically active.

The compounds of the present disclosure include R isomers, S isomers,and mixtures of R and S isomers.

In certain aspects, the compound is of structural Formula (I):

In certain aspects, the compound is of structural Formula (II):

In certain aspects, n is 1; X is O, NH, or CH₂; Z is NH, O, or a directbond; R¹ and R² are each independently hydrogen, halo, or C₁₋₆ alkoxy;R³ is C₁₋₆ alkyl; and R⁴ is hydrogen or C₁₋₆ alkyl.

In certain aspects, n is 1.

In certain aspects, the spacer is ethylene. In further aspects, thespacer is C₁₋₆ alkylene, and wherein one or more of the carbons of theC₁₋₆ alkylene is replaced with O, S, or NR⁶. In certain aspects, one ofthe carbons in the C₁₋₆ alkylene is replaced with an O. In certainaspects, one of the carbons in the C₁₋₆ alkylene is replaced with anNR⁶. In yet further aspects, the spacer is substituted. In some aspects,the spacer is substituted with C₁₋₆ alkyl or ═O.

In certain aspects, X is O, NH, or CH₂. In further aspects, X is O. Infurther aspects, X is NH. In further aspects, X is CH₂.

In certain aspects, Z is NH, O, or a direct bond. In further aspects, Zis a direct bond. In further aspects, Z is O. In further aspects, Z isNH.

In certain aspects, R¹ is hydrogen, halo, or C₁₋₆ alkoxy. In certainaspects, R² is hydrogen, halo, or C₁₋₆ alkoxy. In further aspects, R¹ ishalo and R² is halo. In further aspects, R¹ is Cl and R² is Cl. Infurther aspects, R¹ is hydrogen and R² is C₁₋₆ alkoxy. In furtheraspects, R¹ is hydrogen and R² is ethoxy. In further aspects, R¹ ishydrogen and R² is F. In further aspects, R¹ is F and R² is hydrogen.

In certain aspects, R³ is C₁₋₆ alkyl, wherein one or more of the carbonsof the C₁₋₆ alkyl can optionally be replaced with O. In further aspects,R³ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,methoxy, or ethoxy. In further aspects, R³ is isobutyl.

In certain aspects, R⁴ is hydrogen or C₁₋₆ alkyl. In further aspects, R⁴is hydrogen.

In certain aspects, R⁵ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy. Infurther aspects, R⁵ is C₁₋₆ alkyl. In further aspects, R⁵ is hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or ethoxy.

In certain aspects, the present disclosure providescycloalkylmethylamine derivatives of structural Formulae (III), (IV),(V), (VI), (VII), (VIII), or (IX):

or isomer or pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, 4, or 5;

SP is a spacer, wherein the spacer is C₁₋₆ alkylene, and wherein one ormore of the carbons of the C₁₋₆ alkylene can optionally be replaced withO, S, or NR⁶, wherein R⁶ can be H or C₁₋₆ alkyl;

X is O, S, NH, CH₂, or alkylene;

Z is O, S, NH, CH₂, or a direct bond;

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, C₁₋₆ alkyl,aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl,heteroarylalkyl, acylalkyloxycarbonyl, acyloxyalkyloxycarbonyl,acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, C₁₋₆ alkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonyllalkylamino,alkylasulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino,arylalkylamino, dialkkylamino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, arylloxycarbonylalkoxy,aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate,sulfate, sulfonate, or sulfonamide; optionally R¹, R², R³, R⁴, and R⁵can be substituted with the isotopes ²H (deuterium), ³H (tritium), ¹³C,³⁶Cl, ¹⁸F, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, and ³⁵S; and

“*” denotes a carbon capable of being optically active.

The compounds of the present disclosure include R isomers, S isomers,and mixtures of R and S isomers.

In certain aspects, the compound is of structural Formula (III):

In certain aspects, the compound is of structural Formula (IV):

In certain aspects, the compound is of structural Formula (V):

In certain aspects, the compound is of structural Formula (VI):

In certain aspects, the compound is of structural Formula (VII):

In certain aspects, the compound is of structural Formula Formula(VIII):

In certain aspects, the compound is of structural Formula (IX):

In certain aspects, n is 1; X is O, NH, or CH₂; Z is NH, O, or a directbond; R¹ and R² are each independently hydrogen, halo, or C₁₋₆ alkoxy;R³ is C₁₋₆ alkyl; and R⁴ is hydrogen or C₁₋₆ alkyl.

In certain aspects, n is 1.

In certain aspects, the spacer is ethylene. In further aspects, thespacer is C₁₋₆ alkylene, and wherein one or more of the carbons of theC₁₋₆ alkylene is replaced with O, S, or NR⁶. In certain aspects, one ofthe carbons in the C₁₋₆ alkylene is replaced with an O. In certainaspects, one of the carbons in the C₁₋₆ alkylene is replaced with anNR⁶. In yet further aspects, the spacer is substituted. In some aspects,the spacer is substituted with C₁₋₆ alkyl or ═O.

In certain aspects, X is O, NH, or CH₂. In further aspects, X is O. Infurther aspects, X is NH. In further aspects, X is CH₂.

In certain aspects, Z is NH, O, or a direct bond. In further aspects, Zis a direct bond. In further aspects, Z is O. In further aspects, Z isNH.

In certain aspects, R¹ is hydrogen, halo, or C₁₋₆ alkoxy. In certainaspects, R² is hydrogen, halo, or C₁₋₆ alkoxy. In further aspects, R¹ ishalo and R² is halo. In further aspects, R¹ is Cl and R² is Cl. Infurther aspects, R¹ is hydrogen and R² is C₁₋₆ alkoxy. In furtheraspects, R¹ is hydrogen and R² is ethoxy. In further aspects, R¹ ishydrogen and R² is F. In further aspects, R¹ is F and R² is hydrogen.

In certain aspects, R³ is C₁₋₆ alkyl, wherein one or more of the carbonsof the C₁₋₆ alkyl can optionally be replaced with O. In further aspects,R³ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,methoxy, or ethoxy. In further aspects, R³ is isobutyl.

In certain aspects, R⁴ is hydrogen or C₁₋₆ alkyl. In further aspects, R⁴is hydrogen.

In certain aspects, R⁵ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy. Infurther aspects, R⁵ is C₁₋₆ alkyl. In further aspects, R⁵ is hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or ethoxy.

In certain aspects, the present disclosure providescycloalkylmethylamine derivatives of structural Formulae (X), (XI),(XII), (XIII), (XIV), (XV), (XVI), or (XVII):

or isomer or pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, 4, or 5;

SP is a spacer, wherein the spacer is C₁₋₆ alkylene, and wherein one ormore of the carbons of the C₁₋₆ alkylene can optionally be replaced withO, S, or NR⁶, wherein R⁶ can be H or C₁₋₆ alkyl;

X is O, S, NH, CH₂, or alkylene;

Z is O, S, NH, CH₂, or a direct bond;

R¹, R², R³, R⁴, and R⁵ are each independently hydrogen, C₁₋₆ alkyl,aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryl,heteroarylalkyl, acylalkyloxycarbonyl, acyloxyalkyloxycarbonyl,acylalkyloxycarbonylamino, acyloxyalkyloxycarbonylamino, C₁₋₆ alkoxy,alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonyllalkylamino,alkylasulfinyl, alkylsulfonyl, alkylthio, amino, alkylamino,arylalkylamino, dialkkylamino, arylalkoxy, arylalkoxycarbonylalkoxy,arylalkoxycarbonylalkylamino, aryloxycarbonyl, arylloxycarbonylalkoxy,aryloxycarbonylalkylamino, carboxy, carbamoyl, carbamate, carbonate,cyano, halo, heteroaryloxycarbonyl, hydroxy, phosphate, phosphonate,sulfate, sulfonate, or sulfonamide; optionally R¹, R², R³, R⁴, and R⁵can be substituted with the isotopes ²H (deuterium), ³H (tritium), ¹³C,³⁶Cl, ¹⁸F, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, and ³⁵S; and

“*” denotes a carbon capable of being optically active.

The compounds of the present disclosure include R isomers, S isomers,and mixtures of R and S isomers.

In certain aspects, the compound is of structural Formula Formula (X):

In certain aspects, the compound is of structural Formula (XI):

In certain aspects, the compound is of structural Formula (XII):

In certain aspects, the compound is of structural Formula (XIII):

In certain aspects, the compound is of structural Formula (XIV):

In certain aspects, the compound is of structural Formula (XV):

In certain aspects, the compound is of structural Formula (XVI):

In certain aspects, the compound is of structural Formula (XVII):

In certain aspects, n is 1; X is O, NH, or CH₂; Z is NH, O, or a directbond; R¹ and R² are each independently hydrogen, halo, or C₁₋₆ alkoxy;R³ is C₁₋₆ alkyl; and R⁴ is hydrogen or C₁₋₆ alkyl.

In certain aspects, n is 1.

In certain aspects, the spacer is ethylene. In further aspects, thespacer is C₁₋₆ alkylene, and wherein one or more of the carbons of theC₁₋₆ alkylene is replaced with O, S, or NR⁶. In certain aspects, one ofthe carbons in the C₁₋₆ alkylene is replaced with an O. In certainaspects, one of the carbons in the C₁₋₆ alkylene is replaced with anNR⁶. In yet further aspects, the spacer is substituted. In some aspects,the spacer is substituted with C₁₋₆ alkyl or ═O.

In certain aspects, X is O, NH, or CH₂. In further aspects, X is O. Infurther aspects, X is NH. In further aspects, X is CH₂.

In certain aspects, Z is NH, O, or a direct bond. In further aspects, Zis a direct bond. In further aspects, Z is O. In further aspects, Z isNH.

In certain aspects, R¹ is hydrogen, halo, or C₁₋₆ alkoxy. In certainaspects, R² is hydrogen, halo, or C₁₋₆ alkoxy. In further aspects, R¹ ishalo and R² is halo. In further aspects, R¹ is Cl and R² is Cl. Infurther aspects, R¹ is hydrogen and R² is C₁₋₆ alkoxy. In furtheraspects, R¹ is hydrogen and R² is ethoxy. In further aspects, R¹ ishydrogen and R² is F. In further aspects, R¹ is F and R² is hydrogen.

In certain aspects, R³ is C₁₋₆ alkyl, wherein one or more of the carbonsof the C₁₋₆ alkyl can optionally be replaced with O. In further aspects,R³ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,methoxy, or ethoxy. In further aspects, R³ is isobutyl.

In certain aspects, R⁴ is hydrogen or C₁₋₆ alkyl. In further aspects, R⁴is hydrogen.

In certain aspects, R⁵ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy. Infurther aspects, R⁵ is C₁₋₆ alkyl. In further aspects, R⁵ is hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or ethoxy.

The compounds of this invention described herein can have one or more ofthe following characteristics or properties:

-   -   1. Compounds of the invention can have dopamine transporter        (DAT), norepinephrine transporter (NET) and serotonin        transporter (SERT) inhibitory properties;    -   2. The primary metabolites, regardless of the        electrophysiological properties of the parent drug, has, or        have, negligible inhibitory activity at the IKr (HERG) channel        at the normal therapeutic concentration of the parent drug in        plasma (e.g. the concentration of the metabolite must be at        least five times higher than the normal therapeutic        concentration of the parent compound before activity at the IKr        channel is observed);    -   3. Oral bioavailability of the compounds is consistent with oral        administration using standard pharmacological oral formulations;        however, the compounds, and compositions thereof, can also be        administered using any delivery system that produces constant        and controllable blood levels overt time.

In some embodiments, the subject invention provides compounds having anytwo or more of the above identified characteristics or properties. In apreferred embodiment the compounds of the invention have all fourcharacteristics or properties.

Additional modifications of the compounds disclosed herein can readilybe made by those skilled in the art. Thus, analogs and salts of theexemplified compounds are within the scope of the subject invention.With knowledge of the compounds of the subject invention skilledchemists can use known procedures to synthesize these compounds fromavailable substrates. As used in this application, the term“derivatives” refers to compounds which are substantially the same asanother compound but which may have been modified by, for example,adding additional side groups. The term “derivatives” as used in thisapplication also may refer to compounds which are substantially the sameas another compound but which have atomic or molecular substitution atcertain locations in the compound.

The subject invention further pertains to enantiomerically isolatedcompounds, and compositions comprising the compounds. The isolatedenantiomeric forms of the compounds of the invention are substantiallyfree from one another (i.e., in enantiomeric excess). In other words,the “R” forms of the compounds are substantially free from the “S” formsof the compounds and are, thus, in enantiomeric excess of the “S” forms.Conversely, “S” forms of the compounds are substantially free of “R”forms of the compounds and are, thus, in enantiomeric excess of the “R”forms. In one embodiment of the invention, the isolated enantiomericcompounds are at least about in 80% enantiomeric excess. In a preferredembodiment, the compounds are in at least about 90% enantiomeric excess.In a more preferred embodiment, the compounds are in at least about 95%enantiomeric excess. In an even more preferred embodiment, the compoundsare in at least about 97% enantiomeric excess. In a most preferredembodiment, the compounds are in at least 99% or greater than 99%enantiomeric excess.

Synthesis of the Compounds of the Invention

The compounds of the invention can be obtained via the synthetic methodsillustrated in Schemes 1. Several methods have been described in the artfor the synthesis of cycloalkylmethylamine analogs (see, e.g. Mattson,R. J. et al. U.S. Pat. No. 5,596,019; Lulla, A. et al., InternationalApplication Publication No. WO 2004/096202; Senanayake, C. H. et al.,International Application Publication No. WO 02/083631; Vyas, S. K. etal., International Application Publication No. WO 02/36540; Jerussi, T.P. et al., International Application Publication No. WO 02/060424;Jeffery, J. E. et al., J. Chem. Soc. Perkin Trans 1, 1996, 2583-2589.).Other methods are known in the art for synthesizingcycloalkylmethylamines, which are readily accessible to the skilledartisan. The starting materials and intermediates used in the synthesisof target molecules (Scheme 1-4) thereof are commercially available orcan be prepared by established procedures (See e.g., Green et al.,“Protective Groups in Organic Synthesis,” (Wiley™, 4^(rd) ed., 2006);Harrison et al “Compendium of Synthetic Organic Methods,” vols. 1-8(John Wiley and Sons, 1971-1996); “Beilstein Handbook of OrganicChemistry, Frankfurt, Germany; Feiser et al, “Reagents for OrganicSynthesis,” Volumes 1-45, Karger, 1991; March, Advanced OrganicChemistry,” Wiley Interscience, 4^(th) ed., 1992; Larock “ComprehensiveOrganic Transformations,” Wiley-VCH Publishers, 2^(nd) ed., 1999;Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wileyand Sons, 1^(st) ed., 1995).

Accordingly, starting materials useful for preparing compounds of theinvention and intermediates thereof are commercially available or can beprepared by well-known synthetic methods. Other methods for thesynthesis of cycloalkylmethylamines described herein are eitherdescribed in the art or will be readily apparent to the skilled artisanin view of the references provided above and may be used to synthesizethe compounds of the invention. Accordingly, the methods presented inthe Schemes herein are illustrative rather than comprehensive.

Methods

One general method for synthesis of compounds of Formulae (I) isdescribed in Scheme 1. An appropriate substituted phenylacetonitrile (1)was reacted with dibromoalkane (2) in appropriate solvent (e.g., ether,THF, dioxane, DMF, DMSO) at a temperature between 10 and 100° C.,preferably between 20 and 75° C. in the presence of a base (e.g., NaH,KOH) to give cycloalkylnitrile (3). The cycloalkylnitrile compounds wereused to synthesize compounds (6) using a tandem Grignard-reductionmethod.

The typical procedure involves the reaction of a compound (3) with anappropriate Grignard reagent (R³MgBr) in presence of toluene at a gentlereflux temperature at a for 10 to 24 hours. Then the resulting adductwas subjected to reduction without any workup procedures using reducingagent like sodium borohydride according to a standard or an establishedprocedure (see, Jeffery et al., J. Chem. Soc., Perkin Trans. 1, 1996,2583-2589) to produce the corresponding cycloalkylmethylamine (6). Theselected racemic amine (6) was separated into corresponding opticallypure (R)- and (S)-isomers by a standard chiral crystallization methodusing optically pure tartaric acid. The target cycloalkylmethylaminederivatives (7) were synthesized by alkylation of amines (6) withappropriate alkylating agents (8) or by reductive amination usingappropriate aldehydes (9). The target compounds (7) were converted intocorresponding hydrochloride salts (10) using hydrochloric acid (Scheme1).

In one method cycloalkylmethylamine derivatives comprising Formula (I)was prepared as described in Scheme 2. The cycloalkylmethylamines (6)was alkylated with appropriate 4-nitrosulfonyl ester (18) at roomtemperature to get the corresponding cycloalkylmethylamine derivative(12) in moderato good yields. The compounds (12) were converted intohydrochloride salts by treating with 2N HCl solution in ether understandard conditions.

The key building blocks (18) used in the synthesis ofcycloalkylmethylamine derivatives were synthesized in two steps asillustrated in scheme 3. The carboxylic acids 14 were heated withethylene glycol in presence of catalytic amounts of sulfuric acid to getthe corresponding esters (16) in nearly quantitative yields. Theethylene glycol esters (16) were treated with 4-nitrosulfonyl chloride(17) in presence of a mild base triethylamine in dichloromethane at 0°C. to get the corresponding alkylating agent (18) in good yields.

In another method cycloalkylmethylamine derivatives comprising Formula(I) was prepared as described in Scheme 4. The cycloalkylmethylamine 6were alkylated with appropriate 4-nitrophenylsylfonyloxyethyl carbamate(19) as described for the synthesis cycloalkylmethylamine derivatives(12) in scheme 2 to get the corresponding carbamate derivatives (21) inmoderate yields. The carbamate derivatives (21) were also prepared byreductive alkylation of amines (6) with appropriate aldehydes (20) undermild conditions in moderate to good yields (Scheme 4). The amine (6) wastreated with aldehyde (2) in anhydrous methanol at room temperature for15 hours followed by reacting with sodium borohydride (NaBH₄) at 0° C.to get the corresponding carbamate derivative of cycloalkylmethylamine(21). The selected optically pure (R)-cycloalkylmethylamine derivatives(21c-d) were also prepared from the corresponding optically pure(R)-cycloalkylmethylamines. The selected racemic carbamate derivatives(21) were subjected to chiral HPLC separation to get the correspondingoptically pure (R)- and (S)-carbamates.

The starting building block 4-nitrosulfoxyethanolamine carbamates (19)were prepared as illustrated in scheme 5. N-hydroxysuccinimide wasreacted with appropriate alkyl chloroformate (22) followed byethanolamine to get the carbamate derivatives 24 The carbamates 24 weretreated with 4-nitrosulfonyl chloride in presence of triethylamine indichloromethane to get the corresponding building block carbamates 19 inmoderate to good yields.

Similarly, the aldehyde building blocks (20) used in the preparation of(21) were prepared as illustrated in the scheme 6. The carbamates 27were prepared under identical reaction conditions described forcarbamates 24 in scheme 5. The carbamates were oxidized under mildconditions using commercially available oxidizing agents such aspyridine sulfur trioxide, pyridinium chlorochromate (PCC) or Swernoxidation conditions to get the corresponding aldehydes 20. Theunsubstituted carbamate 29b-c were also prepared from aminoacetaldehydediethyl acetal (28). The carbamate derivatives of acetal 28 wereprepared by reacting with appropriate chloroformate 22 under identicalconditions described for the carbamates 27 in good yields. The carbamatederivatives 29 were treated with 2N hydrochloric acid in ether to getthe corresponding aldehyde 20.

In another method cycloalkylmethylamine derivatives comprising Formula(I) was prepared as described in Scheme 7. The amide derivatives (31) ofcycloalkylmethylamines 6 were synthesized from aldehydes 30 underidentical reductive amination conditions described for carbamatederivatives (21a-c) in scheme 4 in good yields. The racemic amidederivatives (31a-b) were subjected to chiral HPLC separation to get thecorresponding optically pure (R)- and (S)-amides.

The amide building blocks used in the synthesis of cycloalkylmethylaminederivatives 31a-b were prepared as illustrated in scheme 8. Theappropriate carboxylic acids 14 were coupled with aminoacetaldehydediethyl acetal under standard coupling conditions usingN,N-dicyclohexylcarbodiimide (DCC) and N-hydroxyscciniimide (NHS) indichloromethane. The amides 33 were treated with trifluoro acetic acid(TFA) in dichloromethane (DCM) at room temperature to get thecorresponding aldehyde building blocks 30.

In another method cycloalkylmethylamine derivatives comprising Formula(I) was prepared as described in Scheme 9. The cycloalkylmethylamines(6e-f) were subjected to reductive amination with 4-hydroxybutanoate(32) under identical conditions described for the synthesis ofcarbamates (21a-j) in scheme 4 and amides (31a-b) in scheme 7 to get thecorresponding esters (13a-b) in good yields. The esters (13a-b) weretreated with ammonia solution in methanol to get the corresponding amidederivative (33a-b) in good yields. The substituted amides 33c-j weresynthesized by reacting esters (13a-b) with an appropriate amine inpresence of trimethylaluminum (AlMe₃) in toluene as illustrated inscheme 9. The selected racemic amide derivatives (33) were subjected tochiral HPLC separation to get the corresponding optically pure (R)- and(S)-amides.

In another method cycloalkylmethylamine derivatives comprising Formula(I) was prepared as described in Scheme 10. The carbonate derivatives(35a-c) of cycloalkylamines (6e-f) were synthesized from aldehydes (34)using reductive amination conditions as described for the synthesis ofcarbamates (21a-j) in scheme 4 and amides (31a-b) in scheme 7.

The aldehyde building blocks (34) used in the synthesis of the targetcarbonate derivatives (35a-c) were prepared in two steps as illustratedin scheme 11. Ethylene glycol was reacted with appropriate chloroformate(36) in presence of pyridine in dichloromethane to get carbonates (38)in good yields. The carbonates (38) were oxidized under mild conditionsusing pyridine sulfurtrioxide in presence of triethylamine to get thecorresponding aldehydes (34a-b).

Therapeutic Uses of Compounds of Structural Formulae

In various aspects, the present disclosure provides methods of treatingor preventing obesity in a patient, the method comprising administeringto a patient in need of such treatment an effective amount of any one ofthe compounds of structural Formulae (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), or(XVII). In certain aspects, the compound is selected from any one ofstructural Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or(IX). In further aspects, the compound is selected from any one of thecompounds of EXAMPLES 1-87. In further aspects, the method furthercomprises treating an obesity-related co-morbid symptom.

The present invention provides methods of treating and preventingobesity and associated co-morbid conditions. The term “co-morbidconditions associated with obesity” used in this document means medicalconditions known to those skilled in the art to be associated withobesity. The term includes but not limited to the following: diabetesincluding non-insulin dependent diabetes mellitus, impaired glucosetolerance, hypertension, coronary thrombosis, stroke, depression,anxiety, psychoses (for example schizophrenia), tardive dyskinesia, drugaddiction, drug abuse, cognitive disorders, Alzheimer's disease,cerebral ischaemia, obsessive-compulsive behavior, panic attacks, socialphobias, eating disorders such as bulimia, anorexia, snacking and bingeeating, lipid syndromes, hyperglycemia, hyperlipidemia, and stress inmammals particularly humans.

In addition, the compounds, compositions, and methods of the presentinvention can be used in the treatment or prevention of metabolicdiseases and conditions arising therefrom, or for example non exerciseactivity thermogenesis and increased metabolic rate, sexual dysfunction,sleep apnoea, premenstrual syndrome, urinary incontinence includingstress incontinence, hyperactivity disorders, hiatial hernia, and refluxesophagitis, pain, especially neuropathic pain, weight gain associatedwith drug treatment, chronic fatigue syndrome, osteoarthritis and gout,cancers associated with weight gain, menstrual dysfunction, gallstones,orthostatic hypotension and pulmonary hypertension.

The compounds, compositions, and methods of the present invention can beuseful in preventing cardiovascular disease, and in reducing plateletadhesiveness, in aiding weight loss after pregnancy, reducing thecraving to smoke and in aiding weight loss after smoking cessation. Thepresent invention can also be useful in lowering uric acid levels andlipid levels in mammals particularly humans.

In accordance with the invention, a compound and/or a compositioncontaining a compound of structural Formula (I) is administered to apatient, preferably a human, suffering from obesity and associated withco-morbid diseases and/or disorders Further, in certain embodiments, thecompounds and/or compositions of the invention are administered to apatient, preferably a human, as a preventive measure against variousdiseases or disorders. Thus, the compounds and/or compositionscontaining compound(s) of structural Formula (I) may be administered asa preventive measure to a patient having a predisposition for obesityand associated co-morbid diseases and/or disorders (see, Montana, J. G.International Application Publication No. WO 2004/058237; Lulla, A. etal., International Application Publication No. WO 2004/096202; Jerussi,T. P. et al., International Application Publication No. WO 02/060424;Senanayake, C. H. et al., International Application Publication No. WO01/51453; Heal, D. J. International Application Publication No. WO01/00205; Birch, A. M. et al., International Application Publication No.WO 01/00187; Mueller, P. International Application Publication No. WO00/32178; Bailey, C. International Application Publication No. WO98/11884; Kelly, P. International Application Publication No. WO98/13034).

Thus, those of skill in the art may readily assay and use the compoundsand/or compositions containing compound(s) of structural Formulae (I) totreat obesity and associated co-morbid diseases and/or disorders.

In various aspects, the present disclosure provides methods for treatingor preventing depression in a patient, the method comprisingadministering to a patient in need of such treatment an effective amountof any one of the compounds of structural Formulae (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV),(XV), (XVI), or (XVII). In certain aspects, the compound is selectedfrom any one of structural Formulae (I), (II), (X), (XI), (XII), (XIII),(XIV), (XV), (XVI), or (XVII). In further aspects, the compound isselected from any one of the compounds of EXAMPLES 1-87. In furtheraspects, the method further comprises treating a depression-relatedco-morbid symptom.

Therapeutic/Prophylactic Administration

The compounds, and/or compositions containing compounds(s), ofstructural Formula (I) can be advantageously used in human medicine. Aspreviously described in Section 4.4 above, compounds and compositionscontaining compound(s) of structural Formulae (I) are useful for thetreatment or prevention of obesity and associated co-morbid diseasesand/or disorders.

When used to treat or prevent the above disease or disorders compoundsand/or compositions of the invention can be administered or appliedsingly, in combination with other agents. The compounds and/orcompositions of the invention can also be administered or appliedsingly, in combination with other pharmaceutically active agents,including other compounds and/or compositions of the invention.

The current invention provides methods of treatment and prophylaxis byadministration to a patient of a therapeutically effective amount of acomposition and/or compound of the invention. The patient may be ananimal, is more preferably a mammal, and most preferably a human.

The present compounds and/or compositions of the invention, whichcomprise one or more compounds and/or compositions of the invention arepreferably administered orally.

The compounds and/or compositions of the invention may also beadministered by any other convenient route, for example, by infusion orbolus injection, by absorption through epithelial or mucocutaneouslinings (e.g., oral mucosa, rectal and intestinal mucosa, etc.).Administration can be systemic or local. Various delivery systems areknown, (e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc.) that can be used to administer a compound and/orcomposition of the invention. Methods of administration include, but arenot limited to, intradermal, intramuscular, intraperitoneal,intravenous, subcutaneous, intranasal, epidural, oral, sublingual,intranasal, intracerebral, intravabinal, transdermal, rectally, byinhalation, or topically, particularly to the ears, nose, eyes or skin.

In particularly, preferred embodiments, the compounds and/orcompositions of the invention can be delivered via sustained releasesystems, preferably oral sustained release systems. In one embodiment, apump may be used (see, Langer, supra; Sefton, 1987, CRC Crit. RefBiomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J. Med. 321:574).

In another embodiment, polymeric materials can be used (see “MedicalApplications of Controlled Release,” Langer and Wise (eds.), Wiley, NewYork (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. MacromolChem. 23:61; see also Levy et al., 1985, Science 228:190; During et al.,1989, Ann Neurol. 25:351; Howard et al, 1989, J. Neurosurg. 71:105). Ina preferred embodiment, polymeric materials are used for oral sustainedrelease delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropylmethylcellulose). Other preferred cellulose ethershave beendescribed in the art (Bamba et al., Int. J. Pharm., 1979, 2, 307).

In another embodiment, enteric-coated preparations can be used for oralsustained release administration. Preferred coating materials includepolymers with a pH-dependent solubility (i.e., pH-controlled release),polymers with a slow or pH-dependent rate of swelling, dissolution orerosion (i.e., time controlled release), polymers that are degraded byenzymes (i.e., enzyme controlled release) and polymers that form firmlayers that are destroyed by an increase in pressure (i.e.,pressure-controlled release).

In still another embodiment, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.,2000, 26:695-708). In a preferred embodiment, OROS® osmotic deliverysystems sold by Alza Corporation of Mountain View, Calif. are used fororal sustained release delivery devices (See for example, Theeuwes etal., U.S. Pat. No. 3,845,770; and Theeuwes et al, U.S. Pat. No.3,916,899).

In yet another embodiment, a controlled-release system can be placed inproximity of the target of the compounds and/or composition of theinvention, thus requiring only a fraction of the systemic dose (See,e.g., Goodson, in “Medical Applications of Controlled Release,” supra,vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussedin Langer, 1990, Science 249:1527-1533 may also be used.

The compounds, and/or compositions containing compound(s) of structuralFormula (I) of the invention may be cleaved either chemically and/orenzymatically. One or more enzymes present in the stomach, intestinallumen, intestinal tissue, blood, liver, brain or any other suitabletissue of a mammal may enzymatically cleave the compounds and/orcompositions of the invention.

Compositions of the Invention

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of structural Formulae(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),(XII), (XIII), (XIV), (XV), (XVI), or (XVII) and a pharmaceuticallyacceptable carrier, excipient, or diluent.

The present composition contain a therapeutically effective amount ofone or more compounds of the invention, preferably in purified form,together with a suitable amount of a pharmaceutically acceptablevehicle, which so as to provide the form for proper administration to apatient. When administered to a patient, the compounds of the inventionand pharmaceutically acceptable vehicles are preferably sterile. Wateris preferred vehicle when the compound of the invention is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid vehicles, particularly forinjectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present agents, or pH buffering agents.In addition, auxiliary, stabilizing, thickening, lubricating andcoloring agents may be used.

Pharmaceutical compositions comprising a compound of the invention maybe manufactured by means of conventional mixing, dissolving,granulating, dragee-making levigating, and emulsifying, encapsulating,entrapping or lyophilizing process. Pharmaceutical compositions may beformulated in conventional manner using one or more physiologicallyacceptable carriers, diluents, excipients or auxiliaries, whichfacilitate processing of compounds of the invention into preparationswhich can be used pharmaceutically. Proper formulation is dependent uponthe route of administration chosen.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, and capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., Grosswald et al., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical vehicles have been described in theart (see Remington's Pharmaceutical Sciences, Philadelphia College ofPharmacy and Science, 17^(th) Edition, 1985). Preferred compositions ofthe invention are formulated for oral delivery, particularly for oralsustained release administration.

Compositions for oral delivery may be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups or elixirs, for example. Orally administered compositions maycontain one or more optionally agents, for example, sweetening agentssuch as fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry coloring agents and preservingagents to provide a pharmaceutically palatable preparation. Moreover,where in tablet or pill form, the compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract, therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds ofthe invention. In these later platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent or agent composition through an aperture. Thesedelivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such vehiclesare preferably of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout mM to about 50 mM) etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcamitines and the likemay be added.

Compositions for administration via other routes may also becontemplated. For buccal administration, the compositions may take theform of tablets, lozenzes, etc. formulated in conventional manner.Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof the invention with a pharmaceutically acceptable vehicle. Preferably,the pharmaceutically acceptable vehicle is a liquid such as alcohol,water, polyethylene glycol or a perfluorocarbon. Optionally, anothermaterial may be added to alter the aerosol properties of the solution orsuspension of compounds of the invention. Preferably, this material isliquid such as alcohol, glycol, polyglycol or fatty acid. Other methodsof formulating liquid drug solutions or suspension suitable for use inaerosol devices are known to those of skill in the art (see, e.g.,Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611).A compound of the invention may also be formulated in rectal or vaginalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa, butter or otherglycerides. In addition to the formulations described previously, acompound of the invention may also be formulated as depot preparation.Such long acting formulations may be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, a compound of the invention may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

When a compound of the invention is acidic, it may be included in any ofthe above-described formulations as the free acid, a pharmaceuticallyacceptable salt, a solvate or hydrate. Pharmaceutically acceptable saltssubstantially retain the activity of the free acid, may be prepared byreaction with bases and tend to be more soluble in aqueous and otherprotic solvents than the corresponding free acid form.

Methods of Use and Doses

A compound of the invention, or compositions thereof, will generally beused in an amount effective to achieve the intended purpose. For use totreat or prevent obesity and associated co-morbid diseases and/ordisorders the compounds of Formula (I) and compositions containing acompound of Formulae (I) are administered or applied in atherapeutically effective amount.

In various aspects, the present disclosure provides methods of treatingor preventing obesity in a patient, the method comprising administeringto a patient in need of such treatment an effective amount of any one ofthe compounds of structural Formulae (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), or(XVII). In certain aspects, the compound is selected from any one ofstructural Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or(IX). In further aspects, the compound is selected from any one of thecompounds of EXAMPLES 1-87. In further aspects, the method furthercomprises treating an obesity-related co-morbid symptom.

In various aspects, the present disclosure provides methods for treatingor preventing depression in a patient, the method comprisingadministering to a patient in need of such treatment an effective amountof any one of the compounds of structural Formulae (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV),(XV), (XVI), or (XVII). In certain aspects, the compound is selectedfrom any one of structural Formulae (I), (II), (X), (XI), (XII), (XIII),(XIV), (XV), (XVI), or (XVII). In further aspects, the compound isselected from any one of the compounds of EXAMPLES 1-87. In furtheraspects, the method further comprises treating a depression-relatedco-morbid symptom.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques known in the art as previouslydescribed. In addition, in vitro or in vivo assays may optionally beemployed to help identify optimal dosage ranges. The amount of acompound of the invention administered will, of course, is dependent on,among other factors, the subject being treated, and the weight of thesubject, the severity of the affliction, the manner of administrationand the judgment of the prescribing physician. For example, the dosagemay be delivered in a pharmaceutical composition by a singleadministration, by multiple applications or controlled release. In apreferred embodiment, the compounds of the invention are delivered byoral sustained release administration. Preferably, in this embodiment,the compounds of the invention are administered twice per day (morepreferably, once per day). Dosing may be repeated intermittently, may beprovided alone or in combination with other drugs and may continue aslong as required for effective treatment of the disease state ordisorder.

The compounds and/or compositions containing compound(s), of structuralFormulae (I) for the pharmacological treatment of obesity and relatedco-morbid indications may be administered in the range 0.1 mg to 500 mgpreferably 1 mg to 100 mg per day given in one or more doses and morepreferably 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 35 mg or 50 mg per day andmost preferably 25 mg.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. The compounds of the invention may also be demonstrated to beeffective and safe using animal model systems.

Preferably, the therapeutically effective dose of a compound of theinvention described herein will provide therapeutic benefit withoutcausing substantial toxicity. Toxicity of compounds of the invention maybe determined using standard pharmaceutical procedures and may bereadily ascertained by the skilled artisan. The dose ratio between toxicand therapeutic effect is the therapeutic index. A compound of theinvention will preferably exhibit particularly high therapeutic indicesin treating disease and disorders. The dosage of a compound of theinventions described herein will preferably be within a range ofcirculating concentrations that include an effective dose with little orno toxicity.

Exemplary Aspects

The invention is further defined by reference to the following examples,which describe in detail preparation of compounds and compositions ofthe invention and assays for using compounds and compositions of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

Atm=Atmosphere

CDI=1,1′-Carbonyldiimidazole

DCM=dichloromethane

DMAP=4-N,N-dimethylaminopyridine

DMF=N,N-dimethylformamide

g=gram

h=hours

L=liter

LC/MS=liquid chromatography/mass spectroscopy

M=molar

mL=milliliter

mmol=millimols

nM=nanomolar

μM=micromolar

MTBE=methyl tert-butyl ether

rt=room temperature

TEA=triethylamine

THF=tetrahydrofuran

TFA=trifluoroacetic acid

General Procedure for Synthesis of Compounds 6a-g (Scheme 1)

To a stirred solution of Grignard reagent (2M solution in ether, 0 065mol) under nitrogen atmosphere was added drop wise a solution ofphenylcyclobutanecarbonitrile (0.026 mol) in 50 mL of toluene at 0° C.Then the reaction mixture was slowly heated at 92° C. for 18 h. Theprogress of the reaction was monitored by thin layer chromatography(TLC). The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was diluted with 30 mLof anhydrous methanol and cooled down at 0° C., and NaBH₄ (2.5 g) wasadded slowly portion wise. The resulting mixture was stirred untilcomplete conversion of imine intermediate to the corresponding amine.After the reaction was completed, methanol was removed by evaporation.The residue was diluted with ethyl acetate, washed with saturated sodiumbicarbonate, dried over MgSO₄ and evaporated under reduce pressure togive corresponding phenylcyclobutylmethylamine 6 which was purified bycolumn chromatography on silica gel using a gradient of hexane and ethylacetate. The pure products 6a-g gave satisfactory ¹H NMR and/or Massspectral data.

Example 1 1-(1-(4-Chlorophenyl)cyclobutyl)-3-methylbutan-1-amine (6a)

Colorless oil (4.7 g, 72%). ¹HNMR (400 MHz, CDCl₃): δ 0.84 (d, J=6.8 Hz,3H); 0.88 (d, J=6.8 Hz, 3H); 1.13-1.23 (m, 2H); 1.66-1.68 (m, 1H);1.79-1.84 (m, 1H); 1.90-1.96 (m, 1H); 2.15-2.16 (m, 1H); 2.25-2.33 (m,3H); 2.98 (d, J=10.8 Hz, 1H); 7.06 (dd, J=1.6; 8.4 Hz, 2H); 7.24 (dd,J=1.6; 8.4 Hz, 2H). MS (ESI): m/z=252.10 (M+H⁺).

Example 2 1-(1-(2-Fluorophenyl)cyclobutyl)-3-methylbutan-1-amine (6b)

Colorless oil (2.8 g, 70%). ¹HNMR (400 MHz, CDCl₃): δ 0.54-0.61 (m, 1H);0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.14-1.24 (m, 1H);1.66-1.70 (m, 1H); 1.79-1.82 (m, 1H); 1.92-1.99 (m, 1H); 2.13-2.18 (m,1H); 2.26-2.37 (m, 3H); 2.97 (d, J=10.8 Hz, 1H); 6.96 (m, 2H); 7.08 (m,2H). MS (ESI): m/z=236.2 (M+H⁺).

Example 3 1-(1-(3-Fluorophenyl)cyclobutyl)-3-methylbutan-1-amine (6c)

Colorless oil (2.2 g, 70%). ¹HNMR (400 MHz, CDCl₃): δ 0.58-0.65 (m, 1H);0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.15-1.21 (m, 1H);1.67-1.70 (m, 1H); 1.80-1.86 (m, 1H); 1.93-1.98 (m, 1H); 2.12-2.18 (m,1H); 2.28-2.37 (m, 3H); 2.97 (dd, J=2.0 Hz; 10.8 Hz, 1H); 6.82-6.92 (m,3H); 7.21-7.27 (m, 1H). MS (ESI): m/z=236.2 (M+H⁺).

Example 4 1-(1-(4-Fluorophenyl)cyclobutyl)-3-methylbutan-1-amine (6d)

Colorless oil (2.2 g, 70%). ¹HNMR (400 MHz, CDCl₃): δ 0.58-0.65 (m, 1H);0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.15-1.21 (m, 1H);1.67-1.70 (m, 1H); 1.80-1.86 (m, 1H); 1.93-1.98 (m, 1H); 2.12-2.18 (m,1H); 2.28-2.37 (m, 3H); 2.97 (dd, J=2.0 Hz; 10.8 Hz, 1H); 6.93-7.08 (m,3H); 7.12-7.16 (m, 1H). MS (ESI): m/z=236.2 (M+H⁺).

Example 5 1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutan-1-amine(6e)

Colorless oil (3.6 g, 70%). ¹HNMR (400 MHz, CDCl₃): δ 0.53-0.60 (m, 1H);0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.10-1.13 (m, 1H);1.63-1.67 (m, 1H); 1.77-1.83 (m, 1H); 1.91-1.97 (m, 1H); 2.12-2.16 (m,1H); 2.21-2.33 (m, 3H); 2.97 (d, J=10.8 Hz, 1H); 6.96 (dd, J=2.0 Hz; 8.4Hz, 1H); 7.19 (d, J=2 Hz; 1H); 7.32 (d, J=8.4 Hz, 1H). MS (ESI):m/z=287.20 (M+H⁺).

Example 6 1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutan-1-amine (6f)

Colorless oil (1.06 g, 72%). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.64 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.15-1.21 (m, 1H);1.40 (t, J=6.8 Hz, 3H); 1.67-1.69 (m, 1H); 1.79-1.84 (m, 1H); 1.90-1.96(m, 1H); 2.14-2.16 (m, 1H); 2.27-2.36 (m, 3H); 2.98 (dd, J=2.0 Hz; 10.8Hz, 1H); 4.02 (q, J=6.8 Hz, 2H); 6.83 (d, J=8.4 Hz, 2H); 7.05 (d, J=8.4Hz, 2H). MS (ESI): m/z=262.20 (M+H⁺).

Example 7 1-(1-(4-Buthoxyphenyl)cyclobutyl)-3-methylbutan-1-amine (6g)

Colorless oil (2.74 g, 73%). ¹HNMR (400 MHz, CDCl₃): δ 0.56-0.63 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.95 (t, J=7.2 Hz,3H); 1.09 (sbroad, 2H); 1.13-1.20 (m, 1H); 1.43-1.52 (m, 2H); 1.63-1.66(m, 1H); 1.70-1.83 (m, 3H); 1.88-1.96 (m, 1H); 2.10-2.16 (m, 1H);2.25-2.36 (m, 3H); 2.98 (dd, J=2.0 Hz; 10.8 Hz, 1H); 3.93 (t, J=6.4 Hz,2H); 6.82 (d, J=8.4 Hz, 2H); 7.03 (d, J=8.4 Hz, 2H). MS (ESI):m/z=290.20 (M+H⁺).

Example 8 Procedure for Preparation of Optically PureCycloalkylmethylamines 6h-i

The optical pure (R)-isomers of 6h-i were prepared from thecorresponding racemic 6e-g by standard chiral separation method usingcrystallization technique.

(R)-1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutan-1-amine (h)

A mixture of racemic didesmethylsibutramine (7 g, 0.024 mol) and toluene(70 mL) was heated to 70-80° C. and (D)-tartaric acid (3.67 g, 0.024mol) in water (7 mL) and acetone (3.5 mL) was added slowly. Theresulting mixture was refluxed for 30 minutes, after which the water andacetone were removed by distillation. The resulting mixture was cooledto room temperature to provide slurry which was then filtered. Theresulting wet cake was washed two times with MTBE (7 mL×2) and dried toyield (R/S)-DDMS.(D)-TA isolated as an off-white solid (10.72 g, 100%).The (R)-complex complex was submitted to further resolution.

The mixture of (R)-DDMS.(D)-TA (10.72 g) and acetone/water/ethanol (107mL:14.4 mL:7 mL) was refluxed (90° C.) for 1 hour. The mixture was thencooled to room temperature and the resulting slurry was filtered anddried to give (R)-DDMS.(D)-TA isolated as a white solid (3.28 g, 31%).expected ee: 92%. The (R)-compless was submitted to further resolution.

The mixture of (R)-DDMS.(D)-TA (3.28 g, ˜92% ee) andacetonitrile/water/ethanol (39.36 mL:8.52 mL:3.9 mL) was refluxed (90°C.) for 1 hour. The mixture was then cooled to room temperature and theresulting slurry was filtered and dried to give (R)-DDMS.(D)-TA isolatedas a white solid (2.8 g, 85%). Expected ee 99.7%. The mixture wassubmitted to decomplxation

The mixture of (R)-DDMS.(D)-TA (2.809 g) and NaOH (5 mL, 3N) and toluene(25 mL) was stirred for 30 min. The organic phase was washed with water(10 mL), dried over Na₂SO₄ and evaporated to give(R)-1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutan-1-amine ascolorless oil (1.07 g, 58%). The ee was supported by mosher procedure(Ref. U.S. Pat. No. 6,974,838 B2)

Example 9

Colorless oil (1.07 g, 58%). ¹HNMR (400 MHz, CDCl₃): δ 0.53-0.60 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.10-1.13 (m, 1H);1.63-1.67 (m, 1H); 1.77-1.83 (m, 1H); 1.91-1.97 (m, 1H); 2.12-2.16 (m,1H); 2.21-2.33 (m, 3H); 2.97 (d, J=10.8 Hz, 1H); 6.96 (dd, J=2.0 Hz; 8.4Hz, 1H); 7.19 (d, J=2 Hz; 1H); 7.32 (d, J=8.4 Hz, 1H). MS (ESI):m/z=287.20 (M+H⁺).

Example 10 (R)-1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutan-1-amine(6i)

Colorless oil (1.07 g, 58%). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.64 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.15-1.21 (m, 1H);1.40 (t, J=6.8 Hz, 3H); 1.67-1.69 (m, 1H); 1.79-1.84 (m, 1H); 1.90-1.96(m, 1H); 2.14-2.16 (m, 1H); 2.27-2.36 (m, 3H); 2.98 (dd, J=2.0 Hz; 10.8Hz, 1H); 4.02 (q, J=6.8 Hz, 2H); 6.83 (d, J=8.4 Hz, 2H); 7.05 (d, J=8.4Hz, 2H). MS (ESI): m/z=262.2 (M+H⁺).

Example 11 General Procedure for Synthesis of Compounds 12a-y (Scheme 2)

To a stirred solution of cesium carbonate (1.02 g, 5 eq) in 3 mL of DMFwas added appropriate phenylcyclobutylmethylamine (0.00075 mol) and theresulting mixture was stirred at room temperature for 4 hrs. Then asolution 2-(((4-nitrophenyl)sulfonyl)oxy)ethyl ester (0.0025 mol. 4 eq)in 3 mL of DMF was added over a period of 5 minutes. The resultingmixture was stirred at room temperature for overnight. The progress ofthe reaction was monitored by thin layer chromatography (TLC). Thereaction mixture was filtered, diluted with 10 mL of ethyl acetate,washed with brine and dried over Na₂SO₄, evaporated to givecorresponding phenylcyclobutylmethylamine ester 12 which was purified bysilica gel column chromatography using gradient of hexane and ethylacetate. The pure products 12a-y were isolated as colorless thick oil in49-69% yield.

Example 122-((1-(1-(4-Chlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylpropionate (12a)

Colorless oil (0.140 g, 20%). ¹HNMR (400 MHz), CDCl₃): δ 0.62-0.69 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.06-1.09 (m, 1H);1.14 (t, J=7.6 Hz, 3H); 1.60-1.64 (m, 1H); 1.75-1.79 (m, 1H); 1.85-1.91(m, 1H); 2.15-2.17 (m, 1H); 2.24-2.40 (m, 5H); 2.75 (dd, J=2.4 Hz; 10.0Hz, 1H); 2.96-3.00 (m, 2H); 4.12 (t, J=4.4 Hz, 2H); 7.16 (d, J=8.4 Hz,2H); 7.26 (d, J=8.4 Hz, 2H). MS (ESI): m/z=352.20 (M+H⁺).

Example 132-((1-(1-(4-Chlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl butyrate12b (Scheme 2)

Colorless oil (0.12 g, 17%). ¹HNMR (400 MHz), CDCl₃): δ 0.62-0.69 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.92 (t, J=7.6 Hz,3H); 1.06-1.11 (m, 1H); 1.60-1.70 (m, 4H); 1.75-1.79 (m, 1H); 1.86-1.91(m, 1H); 2.15-2.17 (m, 1H); 2.24-2.32 (m, 4H); 2.35-2.39 (m, 1H); 2.75(dd, J=2.4 Hz; 10.0 Hz, 1H); 2.96-3.01 (m, 2H); 4.12 (t, J=4.4 Hz, 2H);7.16 (d, J=8.4 Hz, 2H); 7.26 (d, J=8.4 Hz, 2H). MS (ESI): m/z=366.2(M+H⁺).

Example 142-((1-(1-(4-Chlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylisobutyrate 12c (Scheme 2)

Colorless oil (0.08 g, 20%). ¹HNMR (400 MHz), CDCl₃): d 0.62-0.69 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.06-1.11 (m, 1H);1.18 (d=J=6.4 Hz, 6H); 1.59-1.65 (m, 1H); 1.75-1.79 (m, 1H); 1.88-1.92(m, 1H); 2.15-2.17 (m, 1H); 2.26-2.31 (m, 1H); 2.38-2.40 (m, 1H);2.50-2.60 (m, 3H); 2.74-2.76 (m, 1H); 2.97-3.01 (m, 2H); 4.12 (t, J=4.4Hz, 2H); 7.17 (d, J=8.8 Hz, 2H); 7.26 (d, J=8.8 Hz, 2H). MS (ESI):m/z=366.2 (M+H⁺).

Example 152-((1-(1-(4-Chlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl3-methylbutanoate 12d (Scheme 2)

Colorless oil (0.22 g, 40%). (¹HNMR (400 MHz), CDCl₃): δ 0.62-0.69 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.95 (d, J=6.8 Hz,6H); 0.94-0.95 (m, 1H); 0.98-1.12 (m, 1H); 1.61-1.65 (m, 1H); 1.76-1.80(m, 1H); 1.87-1.92 (m, 1H); 2.05-2.10 (m, 2H); 2.17-2.31 (m, 5H);2.36-2.40 (m, 1H); 2.75 (dd, J=2.4 Hz, 10 Hz, 1H); 2.83-2.94-3.02 (m,2H); 4.10 (t, J=4.4 Hz, 2H); 7.17 (d, J=8.4 Hz, 1H); 7.26 (d, J=8.4 Hz,1H). MS (ESI): m/z=380.2 (M+H⁺).

Example 162-((1-(1-(2-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl acetate12e (Scheme 2)

Colorless oil (0.1 g, 20%). ¹HNMR (400 MHz), CDCl₃): δ 0.63-0.69 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 0.91-0.95 (m, 1H);1.59-1.66 (m, 1H); 1.72-1.81 (m, 1H); 1.85-1.92 (m, 1H); 2.06 (s, 3H);2.12-2.19 (m, 2H); 2.23-2.41 (m, 3H); 2.73 (dd, J=2.8 Hz; 10.0 Hz, 1H);2.97 (t, J=6.4 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 6.90-7.19 (m, 4H). MS(ESI): m/z=322.1 (M+H⁺).

Example 172-((1-(1-(2-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl butyrate12f (Scheme 2)

Colorless oil (0.3 g, 41%). ¹HNMR (400 MHz), CDCl₃): δ 0.62-0.69 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 0.94 (t, J=7.6 Hz,3H); 0.91-0.95 (m, 1H); 1.59-1.68 (m, 3H); 1.75-1.79 (m, 1H); 1.85-1.92(m, 1H); 2.04-2.17 (m, 1H); 2.19-2.37 (m, 5H); 2.73 (dd, J=2.8 Hz; 10.0Hz, 1H); 2.97 (t, J=6.4 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 6.97-7.22 (m,4H). MS (ESI): m/z=350.2 (M+H⁺).

Example 182-((1-(1-(2-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylisobutyrate 12g (Scheme 2)

Colorless oil (0.11 g, 23%). ¹HNMR (400 MHz), CDCl₃): δ 0.84 (d, J=6.8Hz, 6H); 0.91-0.95 (m, 1H); 1.20 (d, J=6.8 Hz, 6H); 1.26-1.31 (m, 2H);1.62-1.69 (m, 1H); 1.79-1.84 (m, 1H); 1.93-2.00 (m, 1H); 2.29-2.42 (m,4H); 2.50-2.57 (m, 1H); 2.84-3.01 (m, 3H); 4.10 (t, J=4.4 Hz, 2H);6.97-7.18 (m, 4H). MS (ESI): m/z=350.2 (M+H⁺).

Example 192-((1-(1-(3-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl acetate12h (Scheme 2)

Colorless oil (0.12 g, 20%). ¹HNMR (400 MHz), CDCl₃): δ 0.63-0.69 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 0.91-0.95 (m, 1H);1.59-1.66 (m, 1H); 1.72-1.81 (m, 1H); 1.85-1.92 (m, 1H); 2.06 (s, 3H);2.12-2.19 (m, 2H); 2.23-2.41 (m, 3H); 2.73 (dd, J=2.8 Hz; 10.0 Hz, 1H);2.97 (t, J=6.4 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 6.97-7.20 (m, 4H). MS(ESI): m/z=322.1 (M+H⁺).

Example 202-((1-(1-(3-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylpropionate 12i (Scheme 2)

Colorless oil (0.11 g, 20%). ¹HNMR (400 MHz), CDCl₃): δ 0.63-0.69 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 0.91-0.95 (m, 1H);1.20 (d, J=7.6 Hz, 3H); 1.59-1.66 (m, 1H); 1.72-1.81 (m, 1H); 1.85-1.92(m, 1H); 2.12-2.19 (m, 2H); 2.23-2.41 (m, 5H); 2.73 (dd, J=2.8 Hz; 10.0Hz, 1H); 2.97 (t, J=6.4 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 6.97-7.20 (m,4H). MS (ESI): m/z=336.1 (M+H⁺).

Example 212-((1-(1-(3-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl butyrate12j (Scheme 2)

Colorless oil (0.2 g, 35%). ¹HNMR (400 MHz), CDCl₃): δ 0.62-0.69 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 0.94 (t, J=7.6 Hz,3H); 0.91-0.95 (m, 1H); 1.59-1.68 (m, 3H); 1.75-1.79 (m, 1H); 1.85-1.92(m, 1H); 2.04-2.17 (m, 1H); 2.19-2.37 (m, 5H); 2.73 (dd, J=2.8 Hz; 10.0Hz, 1H); 2.97 (t, J=6.4 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 6.97-6.98(t-broad, 2H); 7.20-7.21 (t-broad, 2H). MS (ESI): m/z=350.2 (M+H⁺).

Example 222-((1-(1-(3-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylisobutyrate 12k (Scheme 2)

Colorless oil (0.09 g, 22%). ¹HNMR (400 MHz), CDCl₃): δ 0.84 (d, J=6.8Hz, 6H); 0.91-0.95 (m, 1H); 1.20 (d, J=6.8 Hz, 6H); 1.26-1.31 (m, 2H);1.62-1.69 (m, 1H); 1.79-1.84 (m, 1H); 1.93-2.00 (m, 1H); 2.29-2.42 (m,4H); 2.50-2.57 (m, 1H); 2.84-3.01 (m, 3H); 4.10 (t, J=4.4 Hz, 2H);7.06-7.17 (m, 4H). MS (ESI): m/z=350.2 (M+H⁺).

Example 232-((1-(1-(4-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl acetate121 (Scheme 2)

Colorless oil (0.2 g, 38%). ¹HNMR (400 MHz), CDCl₃): δ 0.63-0.69 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 0.91-0.95 (m, 1H);1.59-1.66 (m, 1H); 1.72-1.81 (m, 1H); 1.85-1.92 (m, 1H); 2.06 (s, 3H);2.12-2.19 (m, 2H); 2.23-2.41 (m, 3H); 2.73 (dd, J=2.8 Hz; 10.0 Hz, 1H);2.97 (t, J=6.4 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 6.97 (dd, J=8.4 Hz; 11.6Hz, 1H); 7.06 (dd, J=1.6 Hz; 7.6 Hz, 1H); 7.12-7.17 (m, 2H). MS (ESI):m/z=322.1 (M+H⁺).

Example 242-((1-(1-(4-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylpropionate 12m (Scheme 2)

Colorless oil (0.15 g, 34%). ¹HNMR (400 MHz), CDCl₃): δ 0.63-0.69 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 0.91-0.95 (m, 1H);1.20 (d, J=7.6 Hz, 3H); 1.59-1.66 (m, 1H); 1.72-1.81 (m, 1H); 1.85-1.92(m, 1H); 2.12-2.19 (m, 2H); 2.23-2.41 (m, 5H); 2.73 (dd, J=2.8 Hz; 10.0Hz, 1H); 2.97 (t, J=6.4 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 6.97 (dd, J=1.6Hz; 7.6 Hz, 2H); 7.20 (dd, J=1.6 Hz; 7.6 Hz, 2H). MS (ESI): m/z=336.1(M+H⁺).

Example 252-((1-(1-(4-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl butyrate12n (Scheme 2)

Colorless oil (0.2 g, 40%). ¹HNMR (400 MHz), CDCl₃): δ 0.62-0.69 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 0.94 (t, J=7.6 Hz,3H); 0.91-0.95 (m, 1H); 1.59-1.68 (m, 3H); 1.75-1.79 (m, 1H); 1.85-1.92(m, 1H); 2.04-2.17 (m, 1H); 2.19-2.37 (m, 5H); 2.73 (dd, J=2.8 Hz; 10.0Hz, 1H); 2.97 (t, J=6.4 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 6.97 (dd, J=1.6Hz; 7.6 Hz, 2H); 7.20 (dd, J=1.6 Hz; 7.6 Hz, 2H). MS (ESI): m/z=350.2(M+H⁺).

Example 262-((1-(1-(3-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylisobutyrate 12o (Scheme 2)

Colorless oil (0.1 g, 20%). ¹HNMR (400 MHz), CDCl₃): δ 0.84 (d, J=6.8Hz, 6H); 0.91-0.95 (m, 1H); 1.20 (d, J=6.8 Hz, 6H); 1.26-1.31 (m, 2H);1.62-1.69 (m, 1H); 1.79-1.84 (m, 1H); 1.93-2.00 (m, 1H); 2.29-2.42 (m,4H); 2.50-2.57 (m, 1H); 2.84-3.01 (m, 3H); 4.10 (t, J=4.4 Hz, 2H); 6.97(dd, J=8.4 Hz; 11.6 Hz, 1H); 7.06 (dd, J=1.6 Hz; 7.6 Hz, 1H); 7.12-7.17(m, 2H). MS (ESI): m/z=350.2 (M+H⁺).

Example 272-((1-(1-(3-Fluorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl3-methylbutanoate 12p (Scheme 2)

Colorless oil (91 mg, 13%) ¹HNMR (400 MHz), CDCl₃): δ 0.85 (d, J=6.8 Hz,6H); 0.91-0.95 (m, 1H); 0.95 (d, J=6.8 Hz, 6H); 1.25-1.26 (m, 2H);1.63-1.69 (m, 1H); 1.80-1.84 (m, 1H); 1.93-1.98 (m, 1H); 2.07-2.10 (m,1H); 2.17-2.31 (m, 2H); 2.340-2.40 (m, 4H); 2.83-2.87.01 (m, 3H); 4.10(t, J=4.4 Hz, 2H); 6.97 (dd, J=8.8 Hz; 11.6 Hz, 1H); 7.06 (dd, J=1.6 Hz;7.6 Hz, 1H); 7.12-7.17 (m, 2H). MS (ESI): m/z=364.3 (M+H⁺).

Example 282-((1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylpropionate 12q (Scheme 2)

Colorless oil (94 mg, 14%). ¹HNMR (400 MHz), CDCl₃): δ 0.61-0.68 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.89 (d, J=6.8 Hz, 3H); 1.03-1.04 (m, 1H);1.14 (t, J=7.6 Hz, 3H); 1.62-1.63 (m, 1H); 1.75-1.78 (m, 1H); 1.88-1.91(m, 1H); 2.21-2.38 (m, 6H); 2.75 (dd, J=2.4 Hz; 10.0 Hz, 1H); 2.96-3.02(m, 2H); 4.12 (t, J=4.4 Hz, 2H); 7.06 (dd, J=2.4 Hz; 8.4 Hz, 1H); 7.31(d, J=2.0 Hz, 1H); 7.34 (d, J=8.4 Hz, 1H). MS (ESI): m/z=387.2 (M+H⁺).

Example 292-((1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylbutyrate 12r (Scheme 2)

Colorless oil (0.12 g, 40%). ¹HNMR (400 MHz), CDCl₃): δ 0.62-0.67 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.89 (d, J=6.8 Hz, 3H); 0.96 (t, J=7.6 Hz,3H); 1.04-1.10 (m, 1H); 1.62-1.73 (m, 4H); 1.75-1.82 (m, 1H); 1.88-1.93(m, 1H); 2.10-2.32 (m, 6H); 2.35-2.40 (m, 1H); 2.75 (dd, J=2.4 Hz; 10.0Hz, 1H); 2.95-3.05 (m, 2H); 4.12 (t, J=4.4 Hz, 2H); 7.06 (dd, J=2.0 Hz;8.4 Hz, 1H); 7.31 (d, J=2.0 Hz, 1H); 7.34 (d, J=8.4 Hz, 1H). MS (ESI):m/z=401.3 (M+H⁺).

Example 302-((1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylisobutyrate 12s (Scheme 2)

Colorless oil (0.18 g, 26%). ¹HNMR (400 MHz), CDCl₃): δ 0.52-0.62 (m,1H); 0.78 (d, J=6.8 Hz, 3H); 0.82 (d, J=6.8 Hz, 3H); 0.97-1.04 (m, 1H);1.09 (d=J=6.4 Hz, 6H); 1.53-1.56 (m, 1H); 1.69-1.73 (m, 1H); 1.82-1.85(m, 1H); 2.07-2.17 (m, 1H); 2.15-2.21 (m, 2H); 2.31-2.33 (m, 1H);2.44-2.51 (m, 1H); 2.70 (dd, J=2.4 Hz; 10.0 Hz, 1H); 2.87-3.00 (m, 2H);4.12 (t, J=4.4 Hz, 2H); 7.00 (dd, J=2.4 Hz; 8.4 Hz, 1H); 7.24 (d, J=2.0Hz, 1H); 7.27 (d, J=8.4 Hz, 1H). MS (ESI): m/z=401.3 (M+H⁺).

Example 312-((1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl3-methylbutanoate 12t (Scheme 2)

Colorless oil (0.13 g, 39%). ¹HNMR (400 MHz), CDCl₃): δ 0.85 (d, J=6.8Hz, 6H); 0.91-0.95 (m, 1H); 0.95 (d, J=6.8 Hz, 6H); 1.25-1.26 (m, 2H);1.63-1.69 (m, 1H); 1.80-1.84 (m, 1H); 1.93-1.98 (m, 1H); 2.07-2.10 (m,1H); 2.17-2.31 (m, 2H); 2.340-2.40 (m, 4H); 2.83-2.87.01 (m, 3H); 4.10(t, J=4.4 Hz, 2H); 7.00 (dd, J=2.4 Hz; 8.4 Hz, 1H); 7.24 (d, J=2.0 Hz,1H); 7.27 (d, J=8.4 Hz, 1H). MS (ESI): m/z=415.3 (M+H⁺).

Example 322-((1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethylpropionate 12u (Scheme 2)

Colorless oil (84 mg, 12%). ¹HNMR (400 MHz), CDCl₃): δ 0.65-0.72 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.06-1.10 (m, 1H);1.14 (t, J=7.6 Hz, 3H); 1.40 (t, J=7.2 Hz, 3H); 1.60-1.64 (m, 1H);1.75-1.87 (m, 2H); 2.12-2.16 (m, 1H); 2.27-2.37 (m, 5H); 2.71 (dd, J=2.8Hz; 10.0 Hz, 1H); 2.93-2.99 (m, 2H); 4.02 (q, J=7.2 Hz, 2H); 4.12 (t,J=4.4 Hz, 2H); 6.83 (d, J=8.8 Hz, 2H); 7.15 (d, J=8.8 Hz, 2H). MS (ESI):m/z=362.3 (M+H⁺).

Example 332-((1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethyl butyrate12v (Scheme 2)

Colorless oil (0.2, 40%). ¹HNMR (400 MHz), CDCl₃): δ 0.66-0.72 (m, 1H);0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.94 (t, J=7.6 Hz, 3H);1.06-1.12 (m, 1H); 1.40 (t, J=6.8 Hz, 3H); 1.60-1.69 (m, 3H); 1.75-1.80(m, 1H); 1.82-1.85 (m, 1H); 2.12-2.16 (m, 1H); 2.27-2.37 (m, 5H); 2.71(dd, J=2.8 Hz; 10.0 Hz, 1H); 2.93-2.99 (m, 2H); 4.02 (q, J=7.2 Hz, 2H);4.12 (t, J=4.4 Hz, 2H); 6.83 (d, J=8.8 Hz, 2H); 7.15 (d, J=8.8 Hz, 2H).MS (ESI): m/z=376.3 (M+H⁺).

Example 342-((1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethylisobutyrate 12w (Scheme 2)

Colorless oil (0.15 g, 40%). ¹HNMR (400 MHz), CDCl₃): δ 0.65-0.72 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.06-1.10 (m, 1H);1.07 (d=J=6.4 Hz, 6H); 1.32 (t, J=7.2 Hz, 3H); 1.53-1.59 (m, 1H);1.68-1.73 (m, 1H); 1.75-1.80 (m, 1H); 2.07-2.11 (m, 1H); 2.20-2.30 (m,3H); 2.43-2.50 (m, 1H); 2.65 (dd, J=2.8 Hz; 10.0 Hz, 1H); 2.88-2.94 (m,2H); 3.97 (q, J=7.2 Hz, 2H); 4.03 (t, J=4.4 Hz, 2H); 6.76 (d, J=8.8 Hz,2H); 7.0821 (d, J=8.8 Hz, 2H). MS (ESI): m/z=376.3 (M+H⁺).

Example 352-((1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethyl3-methylbutanoate 12×(Scheme 2)

Colorless oil (0.08 g, 20%). ¹HNMR (400 MHz), CDCl₃): δ 0.65-0.79 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.95 (d=J=6.4 Hz,6H); 1.06-1.12 (m, 1H); 1.23-1.25 (m, 1H); 1.32 (t, J=7.2 Hz, 3H);1.62-1.65 (m, 1H); 1.74-1.79 (m, 1H); 1.82-1.88 (m, 1H); 2.04-2.18 (m,4H); 2.26-2.37 (m, 3H); 2.71 (dd, J=2.8 Hz; 10.0 Hz, 1H); 2.93-3.00 (m,2H); 4.02 (q, J=7.2 Hz, 2H); 4.09 (t, J=4.4 Hz, 2H); 6.83 (d, J=8.4 Hz,2H); 7.0821 (d, J=8.4 Hz, 2H). MS (ESI): m/z=390.3 (M+H⁺).

Example 362-((1-(1-(4-Butoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethylisobutyrate 12y (Scheme 2)

Colorless oil (0.2 g, 39%). ¹HNMR (400 MHz), CDCl₃): δ 0.64-0.71 (m,1H); 0.82 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.96 (t, J=7.2 Hz,3H); 1.04-1.11 (m, 1H); 1.13 (d=J=2.4 Hz, 3H); 1.15 (d, J=2.4 Hz, 3H);1.43-1.52 (m, 2H); 1.60-1.64 (m, 1H); 1.71-1.78 (m, 3H); 1.80-1.86 (m,1H); 2.20-2.22 (m, 1H); 2.24-2.40 (m, 3H); 2.44-2.55 (m, 1H); 2.65 (dd,J=2.8 Hz; 10.0 Hz, 1H); 2.88-3.00 (m, 2H); 3.87 (t, J=7.2 Hz, 2H); 4.03(m, 2H); 6.81 (d, J=8.8 Hz, 2H); 7.0821 (d, J=8.8 Hz, 2H). MS (ESI):m/z=404.3 (M+H⁺).

Example 37 General Procedure for Compounds 16a-b (Scheme 3)

To a suspension of isobutyric acid (5 g, 0.056 mol) and ethylene glycol(15.8 g, 0.283 mol.) was added dropwise Sulfuric acid (cat. 0.4 mL). Theresulting mixture was heated at 80° C. for 4 hrs. The progress of thereaction was monitored by thin layer chromatography (TLC). The reactionmixture was then cooled down to rt, diluted with dichloromethane andwashed with saturated aqueous sodium bicarbonate solution, dried overmagnesium sulfate and evaporated to give 2-hydroxyethyl isobutyrateisolated as a colorless oil.

Example-38 2-Hydroxyethyl isobutyrate 16a

Colorless oil (5.88 g, 78%). ¹HNMR (400 MHz), CDCl₃: δ 1.19 (d, J=6.8Hz, 6H); 2.23 (sbr, 1H); 2.54-2.61 (m, 1H); 3.81 (t, J=4.4 Hz, 2H);4.18-4.20 (m, 2H).

Example 39 2-Hydroxyethyl propionate 16b

Colorless oil (6.2 g, 80%). ¹HNMR (400 MHz), CDCl₃: δ 1.08 (t, J=7.6 Hz,3H); 2.31 (q, J=7.6 Hz, 2H); 2.46 (sbr, 1H); 3.75 (t, J=4.8 Hz, 2H);4.12-4.15 (m, 2H).

Example 40 General Procedure for Synthesis of Compounds 18a-d (Scheme 3)

An appropriate 2-Hydroxyethyl (0.00075 mol.) was dissolved in DCM (5 mL)at 0° C. 4-nitrobenzene-1-sulfonyl chloride (0.167 g, 1 eq) in 5 mL ofDCM was slowly added while the mixture was stirred at ice bath (0-5°C.). Triethylamine (0.158 mL, 1.5 eq) was finally added and the mixturewas continuously stirred at ice bath for 1 h. The progress of thereaction was monitored by TLC. After the reaction was complete, themixture was washed with brine and concentrated using a rotaryevaporator. It was further purified using a column chromatography usinga gradient of ethyl acetate/Hexane to give corresponding purenitrosulphonyl ester 12 as colorless white solid

2-(((4-Nitrophenyl)sulfonyl)oxy)ethyl propionate 18a (Scheme 3)

White solid (0.21 g, 83% yield). ¹HNMR (400 MHz), CDCl₃): δ 1.08 (t,J=7.6 Hz, 3H); 2.31 (q, J=7.6 Hz, 2H); 4.30 (t, J=4.4 Hz, 2H); 4.36 (t,J=4.4 Hz, 2H); 8.13 (d, J=9.2 Hz, 2H); 8.42 (d, J=9.2 Hz, 2H).

Example 41 2-(((4-Nitrophenyl)sulfonyl)oxy)ethyl isobutyrate 18c (Scheme3)

Light yellow solid (1.2 g, 80%). ¹HNMR (400 MHz), CDCl₃): δ 1.19 (d,J=6.8 Hz, 6H); 2.54-2.61 (m, 1H); 4.30 (t, J=4.4 Hz, 2H); 4.36 (t, J=4.4Hz, 2H); 8.13 (d, J=9.2 Hz, 2H); 8.42 (d, J=9.2 Hz, 2H).

General Procedure for Synthesis of Compounds 21a-j

A solution of appropriate phenylcyclobutylmethylamine 6 (0.0009 mol) andcarbamate (0.0009 mol) in methanol anhydrous (10 mL) was stirred for 15hours at room temperature. After the reaction was complete, the reactionmixture was cooled down to 0° C. and NaBH₄ (0.36 g, 5.0 eq) was added.The reaction mixture was stirred for 6 hours from 0° C. to rt, And thenNaHCO₃ solution was added. The product was extracted with ethyl acetate,dried over anhydrous Na₂SO₄ and evaporated under reduced pressure togive ethyl corresponding phenylcyclobutylmethylamine carbamate 21 whichwas purified by silica gel column chromatography using gradient ofhexane and ethyl acetate, isolated as a colorless thick oil in 46-66%yield.

The optical pur (R)-carbamates 21c-d were prepared by usingcorresponding starting optically pur (R)-amine 6e-f. under identicalreaction conditions. The selected carbamates 21a-b were also synthesizedby alternate route by alkylating corresponding amine 6e-i with carbamate19 as described in scheme 4

General Procedure for Synthesis of Compounds 19

To a stirred solution of cesium carbonate (3.5 g, 5 eq) in 5 mL of DMF(anhydrous) was added amine 6e-f (0.6 g, 0.0022 mol. 1 eq) and theresulting mixture was stirred at room temperature for 4 hrs. Then2-((ethoxycarbonyl)amino)ethyl nitrobenzenesulfonate (0.0091 mol. 4 eq)was added. The resulting mixture was stirred at room temperature for twodays. The progress of the reaction was monitored by thin layerchromatography (TLC). The reaction mixture was filtered, diluted with 10mL of ethyl acetate, washed with brine and dried over Na₂SO₄, evaporatedto give the corresponding amine carbamate which was purified by silicagel column chromatography using gradient of DCM/MeOH, isolated as athick oil with 20-40% yield.

Example 42

Ethyl(2-((1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl)carbamate21a (Scheme 4).

Colorless oil (0.180 g, 46%). ¹HNMR (400 MHz), CDCl₃): δ 0.53-0.62 (m,1H); 0.78 (d, J=6.8 Hz, 3H); 0.82 (d, J=6.8 Hz, 3H); 0.99-1.10 (m, 1H);1.18 (t, J=7.2 Hz, 3H); 1.52-1.58 (m, 1H); 1.69-1.74 (m, 1H); 1.80-1.86(m, 1H); 2.04-2.11 (m, 1H); 2.15-2.20 (m, 2H); 2.27-2.34 (m, 1H); 2.67(dd, J=2.4 Hz; 10.0 Hz, 1H); 2.74-2.78 (m 1H); 2.83-2.87 (m, 1H);3.10-3.14 (m, 2H) 4.06 (q, J=6.8 Hz, 2H); 4.95 (sbroad, 1H); 6.99 (dd,J=2.0 Hz; 8.4 Hz, 1H); 7.19 (d, J=2 Hz; 1H); 7.28 (d, J=8.4 Hz, 1H). MS(ESI): m/z=402.2 (M+H⁺).

Example 43 Ethyl(2-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethyl)carbamate21b (Scheme 4)

Colorless oil (0.2 g, 47%). ¹HNMR (400 MHz), CDCl₃): δ 0.64-0.71 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.08-1.13 (m, 1H);1.24 (t, J=7.2 Hz, 3H); 1.42 (t, J=7.2 Hz, 3H); 1.61-1.64 (m, 1H);1.75-1.88 (m, 2H); 2.09-2.16 (m, 1H); 2.29-2.35 (m, 3H); 2.69 (dd, J=2.4Hz; 10.0 Hz, 1H); 2.86 (t, J=5.6 Hz, 2H); 3.17 (q, J=5.6 Hz, 2H); 4.03(q, J=6.8 Hz, 2H); 4.11 (q, J=6.8H, 2H); 5.12 (sbroad, 1H); 6.84 (d,J=8.4 Hz, 2H); 7.14 (d, J=8.4 Hz, 2H). MS (ESI): m/z=377.3 (M+H⁺).

Example 44

(R)-Ethyl(2-((1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl)carbamate21c (Scheme 4)

Colorless oil (0.1 g, 39%). ¹HNMR (400 MHz), CDCl₃): δ 0.53-0.62 (m,1H); 0.78 (d, J=6.8 Hz, 3H); 0.82 (d, J=6.8 Hz, 3H); 0.99-1.10 (m, 1H);1.18 (t, J=7.2 Hz, 3H); 1.52-1.58 (m, 1H); 1.69-1.74 (m, 1H); 1.80-1.86(m, 1H); 2.04-2.11 (m, 1H); 2.15-2.20 (m, 2H); 2.27-2.34 (m, 1H); 2.67(dd, J=2.4 Hz; 10.0 Hz, 1H); 2.74-2.78 (m 1H); 2.83-2.87 (m, 1H);3.10-3.14 (m, 2H) 4.06 (q, J=6.8 Hz, 2H); 4.95 (sbroad, 1H); 6.99 (dd,J=2.0 Hz; 8.4 Hz, 1H); 7.19 (d, J=2 Hz; 1H); 7.28 (d, J=8.4 Hz, 1H). MS(ESI): m/z=402.2 (M+H⁺).

Example 45 (R)-Ethyl(2-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethyl)carbamate21d (Scheme 4)

Colorless oil (0.2 g, 47%). ¹HNMR (400 MHz), CDCl₃): δ 0.64-0.71 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.08-1.13 (m, 1H);1.24 (t, J=7.2 Hz, 3H); 1.42 (t, J=7.2 Hz, 3H); 1.61-1.64 (m, 1H);1.75-1.88 (m, 2H); 2.09-2.16 (m, 1H); 2.29-2.35 (m, 3H); 2.69 (dd, J=2.4Hz; 10.0 Hz, 1H); 2.86 (t, J=5.6 Hz, 2H); 3.17 (q, J=5.6 Hz, 2H); 4.03(q, J=6.8 Hz, 2H); 4.11 (q, J=6.8H, 2H); 5.12 (sbroad, 1H); 6.84 (d,J=8.4 Hz, 2H); 7.14 (d, J=8.4 Hz, 2H). MS (ESI): m/z=377.3 (M+H⁺).

Example 46 Isopropyl(2-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethyl)carbamate21e (Scheme 4)

Colorless oil (0.2 g, 46%) ¹HNMR (400 MHz), CDCl₃): δ 0.61-0.68 (m, 1H);0.82 (d, J=6.8 Hz, 3H); 0.86 (d, J=6.8 Hz, 3H); 1.058-1.12 (m, 1H); 1.21(d, J=6.4 Hz, 6H); 1.39 (t, J=7.2 Hz, 3H); 1.58-1.65 (m, 1H); 1.70-1.87(m, 2H); 2.05-2.14 (m, 1H); 2.26-2.34 (m, 3H); 2.67 (dd, J=2.4 Hz; 10.0Hz, 1H); 2.84 (t, J=5.6 Hz, 2H); 3.14 (q, J=5.6 Hz, 2H); 4.01 (q, J=6.8Hz, 2H); 4.86-4.92 (m, 1H); 5.05 (sbroad, 1H); 6.84 (d, J=8.4 Hz, 2H);7.14 (d, J=8.4 Hz, 2H). MS (ESI): m/z=391.3 (M+H⁺).

Example 47

Isopropyl(2-((1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl)carbamate21f (Scheme 4)

Colorless oil (0.3 g, 50%). ¹HNMR (400 MHz), CDCl₃): δ 0.59-0.65 (m,1H); 0.83 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.03-1.09 (m, 1H);1.21 (d, J=6.4 Hz, 6H); 1.58-1.64 (m, 1H); 1.73-1.78 (m, 1H); 1.85-1.91(m, 1H); 2.12-2.16 (m, 1H); 2.23-2.26 (m, 2H); 2.32-2.37 (m, 1H); 2.72(dd, J=2.4 Hz; 10.0 Hz, 1H); 2.79-2.83 (m 1H); 2.88-2.93 (m, 1H);3.16-3.19 (m, 2H) 4.88-4.93 (m, 1H); 4.95 (sbroad, 1H); 6.99 (dd, J=2.0Hz; 8.4 Hz, 1H); 7.19 (d, J=2 Hz; 1H); 7.28 (d, J=8.4 Hz, 1H). MS (ESI):m/z=416.3 (M+H⁺).

Example 48

Ethyl(1-((1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino-2-methylpropan-2-yl)carbamate21g (Scheme 4)

Colorless oil (0.728 g, 90%). ¹HNMR (400 MHz), CDCl₃): δ 0.53-0.62 (m,1H); 0.78 (d, J=6.8 Hz, 3H); 0.82 (d, J=6.8 Hz, 3H); 0.99-1.10 (m, 1H);1.18 (t, J=7.2 Hz, 3H); 1.26 (s, 3H); 1.38 (s, 3H); 1.52-1.58 (m, 2H);1.69-1.74 (m, 1H); 1.80-1.86 (m, 1H); 2.04-2.11 (m, 1H); 2.15-2.20 (m,2H); 2.27-2.34 (m, 1H); 2.64-88 (m, 3H); 4.06 (q, J=7.2 Hz, 2H); 5.20(sbroad, 1H); 6.99 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.19 (d, J=2 Hz; 1H);7.28 (d, J=8.4 Hz, 1H). MS (ESI): m/z=430.3 (M+H⁺).

Example 49Isopropyl(1-((1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino-2-methylpropan-2-yl)carbamate21h (Scheme 4)

Colorless oil (0.4 g, 70%). ¹HNMR (400 MHz), CDCl₃): δ 0.53-0.62 (m,1H); 0.78 (d, J=6.8 Hz, 3H); 0.82 (d, J=6.8 Hz, 3H); 0.99-1.10 (m, 1H);1.22 (d, J=6.4 Hz, 6H); 1.27 (d, J=6.4 Hz, 6H); 1.34 (sbroad, 1H);1.52-1.58 (m, 1H); 1.69-1.74 (m, 1H); 1.80-1.86 (m, 1H); 2.04-2.11 (m,1H); 2.15-2.20 (m, 2H); 2.27-2.34 (m, 1H); 2.64-88 (m, 3H); 4.57-4.60(m, 1H); 5.09 (sbroad, 1H); 6.99 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.19 (d,J=2 Hz; 1H); 7.28 (d, J=8.4 Hz, 1H). MS (ESI): m/z=444.3 (M+H⁺).

Example 50

Ethyl(1-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino-2-methylpropan-2-yl)carbamate21i (Scheme 4)

Colorless oil (0.27 g, 80%). ¹HNMR (400 MHz), CDCl₃): δ 0.64-0.71 (m,1H); 0.84 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 1.08-1.13 (m, 1H);1.18 (s, 3H); 1.20 (s, 3H); 1.24 (t, J=7.2 Hz, 3H); 1.42 (t, J=7.2 Hz,3H); 1.55-1.64 (m, 2H); 1.67-1.71 (m, 1H); 1.75-1.88 (m, 1H); 2.09-2.16(m, 1H); 2.29-2.35 (m, 3H); 2.63-2.67 (m, 2H); 2.71 (d, J=12.0 Hz, 1H);3.94-3.99 (m, 4H); 5.40 (s, 1H); 6.84 (d, J=8.4 Hz, 2H); 7.14 (d, J=8.4Hz, 2H). MS (ESI): m/z=405.3 (M+H⁺).

Example 51

Isopropyl(1-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino-2-methylpropan-2-yl)carbamate21j (Scheme 4)

Colorless oil (0.27 g, 62%). ¹HNMR (400 MHz), CDCl₃): δ 0.55-0.62 (m,1H); 0.78 (d, J=6.8 Hz, 3H); 0.84 (d, J=6.8 Hz, 3H); 1.08-1.13 (m, 1H);1.22 (d, J=6.4 Hz, 6H); 1.25 (d, J=6.4 Hz, 6H); 1.42 (t, J=7.2 Hz, 3H);1.54 (sbroad, 1H), 1.55-1.64 (m, 1H); 1.67-1.71 (m, 1H); 1.75-1.88 (m,1H); 2.09-2.16 (m, 1H); 2.29-2.35 (m, 3H); 2.63-2.67 (m, 2H); 2.71 (d,J=11.6 Hz, 1H); 3.97 (q, J=7.2 Hz, 2H); 4.75-4.80 (m, 1H); 5.40 (s, 1H);6.84 (d, J=8.4 Hz, 2H); 7.14 (d, J=8.4 Hz, 2H). MS (ESI): m/z=419.3(M+H⁺).

Example 52 Ethyl (2-hydroxyethyl)carbamate 24a (Scheme 5)

To a stirred solution of ethyl chloroformate (4 g, 0.037 mol.) andN-hydroxysuccinimide (6.3 g, 0.055 mol.) in 10 mL of DCM at 0° C. undernitrogen atmosphere was added N,N-Diisopropylethylamine (9.5 g, 0.055mol) in 10 mL of DCM. The progress of the reaction was monitored by thinlayer chromatography (TLC). After stirring for 3 hrs at roomtemperature, the reaction mixture was filtered and the precipitate waswashed with 2×10 mL of dichloromethane. The combined filtrate wasevaporated and dissolved in 20 mL of acetonitrile, cooled in an ice-bathand then added dropwise a solution of Ethanolamine 23 (3.3 mL, 2.5 eq).The resulting mixture was stirred at ice-bath temperature for 1 h andthen overnight at room temperature. The progress of the reaction wasmonitored by thin layer chromatography (TLC). The reaction mixture wasfiltered, and the precipitate was washed with 2×10 mL DCM and dried oversodium sulfate. After removing the solvent under reduced pressure, theresidue was purified by silica gel column chromatography to give ethyl(2-hydroxyethyl)carbamate.

Colorless oil (4.3 g, 88%). ¹HNMR (400 MHz), CDCl₃: δ 1.20 (t, J=7.2 Hz,3H); 3.2 (sbr, 1H); 3.27 (q, J=5.2 Hz, 2H); 3.65 (t, J=4.8 Hz, 2H); 4.07(q, J=7.2 Hz, 2H); 5.38 (sbr, 1H).

Example 53 Isopropyl (2-hydroxyethyl)carbamate 24b (Scheme 5)

Colorless oil (4.2 g, 87%). ¹HNMR (400 MHz), CDCl₃: δ 1.20 (d, J=6.0 Hz,6H); 2.85 (sbr, 1H); 3.28 (q, J=5.2 Hz, 2H); 3.66 (t, J=5.2 Hz, 2H);4.88-4.90 (m, 1H); 5.17 (sbr, 1H).

Example 54 General Procedure for Synthesis of Compounds 19

Ethyl (2-hydroxyethyl) carbamate (0.7 g, 0.0052 mol.) was dissolved inDCM (10 mL) at 0° C. 4-nitrobenzene-1-sulfonyl chloride (1.2 g, 1.1 eq)in 10 mL of DCM was slowly added while the mixture was stirred at icebath (0-5° C.). Pyridine (2.1 mL, 5 eq) was finally added and themixture was continuously stirred at ice bath for 4 h. The progress ofthe reaction was monitored by TLC. After the reaction was complete, themixture was wash with water and concentrated using a rotary evaporator.It was further purified using a column chromatography (silicagel-AcOEt/Hexane) to give 2-((ethoxycarbonyl)amino)ethyl4-nitrobenzenesulfonate light yellow solid.

2-((Ethoxycarbony)amino)ethyl 4-nitrobenzenesulfonate 19 (Scheme 5)

Light yellow solid (1.2 g, 75%). ¹HNMR (400 MHz), CDCl₃: δ 1.22 (t,J=7.2.8 Hz, 3H); 3.47 (q, J=5.2 Hz, 2H); 4.07 (q, J=7.2 Hz, 2H); 3.20(t, J=5.2 Hz, 2H); 4.93 (sbr, 1H); 8.10 (d, J=9.2 Hz, 2H); 8.40 (d,J=9.2 Hz, 2H).

Example 55 General Procedure for Compounds 29

To a stirred solution of ethyl chloroformate (3 g, 0.027 mol.) andN-hydroxysuccinimide (3.8 g, 0.033 mol.) in 10 mL of DCM at 0° C. undernitrogen atmosphere was added N,N-Diisopropylethylamine (7.0 mL, 0.04mol). The progress of the reaction was monitored by thin layerchromatography (TLC). After stirring for 3 hrs at room temperature. DCMwas evaporated and the residue was dissolved in 10 mL of acetonitrile,cooled in an ice-bath and then added dropwise a solution ofaminoacetaldehyde diethyl acetal (4.7 mL, 1.2 eq). The resulting mixturewas stirred at ice-bath temperature for 1 h and then overnight at roomtemperature. The progress of the reaction was monitored by thin layerchromatography (TLC). The reaction mixture was filtered, and theprecipitate was washed with 2×10 mL DCM and dried over sodium sulfate.After removing the solvent under reduce pressure, the residue waspurified by silica gel column chromatography to give ethyl(2,2-diethoxyethyl)carbamate as a colorless oil

Ethyl (2,2-diethoxyethyl)carbamate 29 (Scheme 6)

Colorless oil (5.17 g, 94% yield). ¹HNMR (400 MHz), CDCl₃: δ 1.18 (t,J=7.2 Hz, 6H); 1.20 (t, J=7.2 Hz, 3H); 3.26 (t, J=5.6 Hz, 2H); 3.51 (q,J=7.2 Hz, 2H); 3.64 (q, J=7.2 Hz, 2H); 4.08 (q, J=7.2 Hz, 2H); 4.46 (t,J=5.2 Hz, 1H); 4.87 (sbr, 1H).

Example 56 General Procedure for Compounds 27

To a stirred solution of ethyl chloroformate (3 g, 0.027 mol.) andN-hydroxysuccinimide (3.8 g, 0.033 mol.) in 10 mL of DCM at 0° C. undernitrogen atmosphere was added N,N-Diisopropylethylamine (7.0 mL, 0.04mol). The progress of the reaction was monitored by thin layerchromatography (TLC). After stirring for 3 hrs at room temperature. DCMwas evaporated and the residue was dissolved in 10 mL of acetonitrile,cooled in an ice-bath and then added dropwise a solution of2-amino-2-methyl-1-propanol (3.1 mL, 1.2 eq). The resulting mixture wasstirred at ice-bath temperature for 1 h and then overnight at roomtemperature. The progress of the reaction was monitored by thin layerchromatography (TLC). The reaction mixture was filtered, and theprecipitate was washed with 2×10 mL DCM and dried over sodium sulfate.After removing the solvent under reduce pressure, the residue waspurified by silica gel column chromatography to give ethyl(1-hydroxy-2-methylpropan-2-yl)carbamate as a colorless oil

Ethyl (1-hydroxy-2-methylpropan-2-yl)carbamate 27 (Scheme 6)

Colorless oil (3.63 g, 82%). ¹HNMR (400 MHz), CDCl₃: δ 1.18 (t, J=7.2Hz, 3H); 1.22 (s, 6H); 3.53 (d, J=6.0 Hz, 2H); 3.9 (sbroad, 1H); 4.00(q, J=7.2 Hz, 2H); 4.91 (sbroad, 1H).

Example 57 Isopropyl (1-hydroxy-2-methylpropan-2-yl)carbamate 27 (Scheme6)

Colorless oil (2.8 g, 90%). ¹HNMR (400 MHz), CDCl₃: δ 1.20 (d, J=6.4 Hz,6H); 1.22 (s, 6H); 3.53 (d, J=6.0 Hz, 2H); 3.9 (sbroad, 1H); 4.82-4.88(m, 1H); 4.91 (sbroad, 1H).

Example 58 Ethyl (2-oxoethyl)carbamate 20a (Scheme 6)

Procedure 1: A solution of ethyl (2,2-diethoxyethyl)carbamate (2.0 g,0.0097 mol.)) in 5 mL of THF at 0° C. was added HCl (10 mL, 2.0 eq) andthen H₂O (0.17 mL). The solution was then stirred for 4 h at 0° C. thesolvent was evaporated at room temperature and solid NaHCO₃ was added,filtration and concentration to give after silica gel chromatographyethyl (2-oxoethyl)carbamate as a colorless oil (0.36 g, 28%). ¹HNMR (400MHz), CDCl₃: 8 1.19 (t, J=7.2 Hz, 3H); 4.05-4.10 (m, 4H); 5.44 (sbr,1H); 9.60 (s, 1H).

Procedure 2: To an ice-cooled and stirred solution of ethyl(1-hydroxy-2-methylpropan-2-yl)carbamate and triethylamine (1.7 mL, 2eq) in DMSO (5 mL) was added portionwise a solution of SO₃.Py (1.9 g,0.012 mol.) in DMSO (5 mL), and the whole was stirred at roomtemperature for 1 h. The progress of the reaction was monitored by thinlayer chromatography (TLC). After the reaction was completed, thereaction mixture was poured into ice-water solution and extracted withethyl acetate. The extracted was washed successively with aqueous HCl(0.5N), NaHCO₃ solution and brine, dried over MgSO₄, and concentratedunder reduce pressure. The residue was purified by silica gelchromatography using gradient of hexane and ethyl acetate, ethyl(2-oxopropan-2-yl)carbamate as a colorless oil (0.129 g, 28% yield).¹HNMR (400 MHz), CDCl₃: δ 1.19 (t, J=7.2 Hz, 3H); 4.05-4.10 (m, 4H);5.44 (sbr, 1H); 9.60 (s, 1H).

Example 59 Isopropyl (2-oxoethyl)carbamate 20b (Scheme 6)

Synthesized according to procedure 2 used for 20a. Colorless oil (0.15g, 13% yield). ¹HNMR (400 MHz), CDCl₃: δ 1.22 (d, J=6.0 Hz, 6H); 4.09(t, J=4.4 Hz, 2H); 4.86-4.93 (m, 1H); 5.25 (sbr, 1H); 9.63 (s, 1H).

Example 60 Ethyl (2-methyl-1-oxopropan-2-yl)carbamate 20c (Scheme 6)

Synthesized according to procedure 2 used for 20a. Colorless oil (0.64g, 66% yield). ¹HNMR (400 MHz), CDCl₃: δ 1.21 (t, J=7.2 Hz, 3H); 1.35(s, 6H); 4.08 (q, J=7.2 Hz, 2H); 5.21 (sbroad, 1H); 9.40 (s, 1H).

Example 61 Isopropyl (2-methyl-1-oxopropan-2-yl)carbamate 20d (Scheme 6)

Synthesized according to procedure 2 used for 20a. Colorless oil (1.18g, 60% yield). ¹HNMR (400 MHz), CDCl₃: δ 1.20 (d, J=6.8 Hz, 6H); 1.33(s, 6H); 4.85-4.88 (m, 1H); 5.10 (sbroad, 1H); 9.40 (s, 1H).

Example 62

N-(2-((1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl)butyramide31a (Scheme 7)

A solution of1-(1-(3,4-dichlorophenyl))cyclobutyl)-3-methylbutan-1-amine (0.5 g,0.0017 mol) and N-(2-oxoethyl)butyramide (0.225 g, 0.0017 mol) inEthanol anhydrous (10 mL) was stirred for 15 hours at 60° C. After thereaction was completed, the reaction mixture was cooled down to 0° C.and NaBH₄ (0.32 g, 5.0 eq) was added. The reaction mixture was stirredfor 6 hours from 0° C. to rt, And then NaHCO₃ solution was added. Theproduct was extracted with ethyl acetate, dried over Na₂SO₄ andevaporated under reduced pressure to giveN-(2-((1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethyl)butyramidewhich was purified by silica gel column chromatography using gradient ofDichloromethane and methanol (0% to 1%) and then hexane ethyl acetate(50% to 100%), isolated as a colorless oil (0.180 g, 20%).

¹HNMR (400 MHz), CDCl₃): δ 0.60-0.67 (m, 1H); 0.84 (d, J=6.8 Hz, 3H);0.88 (d, J=6.8 Hz, 3H); 0.94 (t, J=7.2 Hz, 3H); 1.05-1.12 (m, 1H);1.61-1.67 (m, 3H); 1.74-1.80 (m, 1H); 1.83-1.92 (m, 1H); 2.16 (t, J=7.2Hz, 3H); 2.22-2.29 (m, 2H); 2.32-2.37 (m, 1H); 2.73 (dd, J=2.4 Hz; 10.0Hz, 1H); 2.80-2.86 (m 1H); 2.88-2.94 (m, 1H); 3.23-3.30 (m, 2H); 5.94(sbroad, 1H); 7.03 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.28 (d, J=2 Hz; 1H);7.34 (d, J=8.4 Hz, 1H). MS (ESI): m/z=400.3 (M+H⁺).

Example 63N-(2-((1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethyl)butyramide31b (Scheme 7)

Colorless oil (0.07, 27%). ¹HNMR (400 MHz), CDCl₃): δ 0.64-0.71 (m, 1H);0.83 (d, J=6.8 Hz, 3H); 0.88 (d, J=6.8 Hz, 3H); 0.93 (t, J=7.6 Hz, 3H);1.08-1.14 (m, 1H); 1.39 (t, J=7.2 Hz, 3H); 1.59-1.68 (m, 3H); 1.74-1.79(m, 1H); 1.81-1.84 (m, 1H); 2.10-2.15 (m, 3H); 2.28-2.33 (m, 3H); 2.69(dd, J=2.4 Hz; 10.0 Hz, 1H); 2.83-2.88 (m, 2H); 3.20-3.25 (m, 2H); 4.03(q, J=6.8 Hz, 2H); 6.50 (sbroad, 1H); 6.83 (d, J=8.8 Hz, 2H); 7.12 (d,J=8.8 Hz, 2H). MS (ESI): m/z=375.3 (M+H⁺).

Example 64 N-(2-Oxoethyl)butyramide 30 (Scheme 8)

A solution of N-(2,2-diethoxyethyl)butyramide (2.0 g, 0.0098 mol.)) in10 mL of THF at 0° C. was added HCl (2N) in ether (4.9 mL, 1.0 eq) andwater (0.34 mL, 2 eq). The solution was then stirred for 2 to 3 h at 0°C. the solvent was evaporated at room temperature and solid NaHCO₃ wasadded, filtration and concentration to give after silica gelchromatography N-(2-oxoethyl)butyramide as a colorless oil (0.55 g g,55% yield). ¹HNMR (400 MHz, CDCl₃): δ 0.89 (t, J=7.2 Hz, 3H); 1.58-1.63(m, 2H); 2.12 (t, J=7.2 Hz, 2H); 4.17 (d, J=5.2 Hz, 2H); 6.31 (sbroad,1H); 9.63 (s, 1H).

Example 65 Methyl 4-oxobutanoate 32 (Scheme 9)

To a stirred solution of DMSO (2.9 mL., 4.4 eq) in 10 mL of DCManhydrous at −75° C. was added drop by drop a solution of oxalylchloride (1.7 mL, 2.2 eq). After 1 hour of reaction, methyl4-hydroxybutanoate (1.1 g, 0.0093 mol.) in 10 mL of DCM was added. Afterthe addition was completed, the reaction mixture was stirred for 1 hour,warm-up to −45° C. and then triethylamine (7.7 mL, 6 eq)) was added. Thereaction mixture was stirred for 18 hours. The progress of the reactionwas monitored by thin layer chromatography (TLC). After the reaction wascomplete, saturated sodium bicarbonate was added and extracted with DCM.The Organic layer was dried over Na₂SO₄ and concentrated on rotavap togive methyl 4-oxobutanoate which was purified by silica gelchromatography using gradient of hexane and ethyl acetate.

Colorless oil (0.57 g, 53% yield). ¹HNMR (400 MHz, CDCl₃): δ 2.60 (t,J=6.8 Hz, 2H); 2.77 (t, J=6.8 Hz, 2H); 3.66 (s, 3H); 9.78 (s, 1H).

Example 66 General Procedure for Compounds 13 (Scheme 9) Methyl4-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)butanoate 13a(Scheme 9)

A solution of 1-(1-(4-ethoxyphenyl))cyclobutyl)-3-methylbutan-1-anamine(0.619 g, 0.0023 mol) and methyl 4-oxobutanoate (0.25 g, 0.0021 mol) inmethanol anhydrous (10 mL) was stirred for 15 hour at reflux. Thereaction mixture was cooled down to 0° C., And then NaBH₄ (0.4 g, 5 eq)was added. The reaction mixture was stirred from 0° C. to roomtemperature for 4 hours. The progress of the reaction was monitored bythin layer chromatography (TLC). After the reaction was completed, thereaction mixture was concentrated under reduce pressure. The residue wastaken with Ethyl acetate and then washed with NaHCO₃ solution. driedover Na₂SO₄ and evaporated under reduced pressure to give methyl4-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)butanoate whichwas purified by silica gel column chromatography using gradient ofhexane and ethyl acetate, isolated as a (0.55 g, 73% yield).

¹HNMR (400 MHz, CDCl₃): δ 0.59-0.66 (m, 1H); 0.80 (d, J=6.8 Hz, 3H);0.85 (d, J=6.8 Hz, 3H); 1.02-1.08 (m, 1H); 1.39 (t, J=6.8 Hz, 3H);1.59-1.63 (m, 1H); 1.67-1.76 (m, 3H); 1.79-1.85 (m, 1H); 2.10-2.14 (m,1H); 2.24-2.34 (m, 3H); 2.36-2.40 (m, 2H); 2.66 (dd, J=2.8 Hz; 10 Hz,1H); 2.74 (t, J=6.8 Hz, 2H); 3.65 (s, 3H); 4.01 (q, J=7.2 Hz, 2H); 6.82(d, J=8.8 Hz, 2H); 7.12 (d, J=8.8 Hz, 2H). MS (ESI): m/z=362.3 (M+H⁺).

Example 67 Methyl4-((1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)butanoate13b (Scheme 9)

Colorless oil (0.47 g, 70%). ¹HNMR (400 MHz, CDCl₃): δ 0.59-0.66 (m,1H); 0.80 (d, J=6.8 Hz, 3H); 0.85 (d, J=6.8 Hz, 3H); 1.02-1.08 (m, 1H);1.59-1.63 (m, 1H); 1.67-1.76 (m, 3H); 1.79-1.85 (m, 1H); 2.10-2.14 (m,1H); 2.24-2.34 (m, 3H); 2.36-2.40 (m, 2H); 2.66 (dd, J=2.8 Hz; 10 Hz,1H); 2.74 (t, J=6.8 Hz, 2H); 3.65 (s, 3H); 6.98 (d, J=8.4 Hz, 1H); 7.22(s, 1H); 7.36 (d, J=8.4 Hz, 1H). MS (ESI): m/z=387.3 (M+H⁺).

Example 68 General Procedure for Compounds 33a-b4-((1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)butanamide 33a(Scheme 9)

A solution of methyl4-((1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)butanoate(0.50 g) and ammonia, 7N in methanol (30 mL) (excess) was taken in asealed tube. The reaction mixture was reflux (70° C.) for 15 h. Afterthe reaction was completed, the solvent was evaporated. The residue waspurified by silica gel chromatography to give4-((1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)butanamide asa colorless oil (0.62 g, 67%).

¹HNMR (400 MHz, CDCl₃): δ 0.57-0.64 (m, 1H); 0.82 (d, J=6.8 Hz, 3H);0.87 (d, J=6.8 Hz, 3H); 1.04-1.07 (m, 1H); 1.55-1.63 (m, 1H); 1.71-1.79(m, 3H); 1.82-1.92 (m, 1H); 2.08-2.15 (m, 1H); 2.18-2.40 (m, 5H);2.70-2.75 (m, 2H); 2.80-2.86 (m, 1H); 5.42 (sbroad, 1H); 5.70 (sbroad,1H); 7.03 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.29 (d, J=2.0 Hz, 1H); 7.33 (d,J=8.4 Hz, 1H). MS (ESI): m/z=372.3 (M+H⁺).

Example 69(R)-4-((1-(1-3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)butanamide-(Isomer-1)

Separated by chiral HPLC method. Colorless oil (0.08 g, 45%). ¹HNMR (400MHz, DMSO): δ 0.53-0.59 (m, 1H); 0.78 (d, J=6.8 Hz, 3H); 0.83 (d, J=6.8Hz, 3H); 0.92-0.98 (m, 1H); 1.58-1.69 (m, 4H); 1.84-1.86 (m, 1H);2.09-2.11 (m, 5H); 2.18-2.20 (m, 2H); 2.33-3.73 (m, 4H); 6.67 (sbroad,1H); 7.20 (dd, J=2.0 Hz; 8.4 Hz, 1H); 7.41 (d, J=2.0 Hz, 1H). 7.52 (d,J=8.4 Hz, 1H). MS (ESI): m/z=372.3 (M+H⁺).

Example 70(S)-4-(1-(1-3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)butanamide-(Isomer-2)

Separated by chiral HPLC method. Colorless oil (0.07 g, 38%). ¹HNMR (400MHz, DMSO): δ 0.54-0.59 (m, 1H); 0.78 (d, J=6.8 Hz, 3H); 0.83 (d, J=6.8Hz, 3H); 0.93-0.99 (m, 1H); 1.57-1.69 (m, 4H); 1.84-1.87 (m, 1H);2.07-2.14 (m, 4H); 2.18-2.22 (m, 1H); 2.33-2.40 (m, 1H); 2.58-3.32 (m,3H); 4.33 (d, J=4 Hz, 1H); 6.67 (sbroad, 1H); 7.19 (dd, J=1.6 Hz; 8.4Hz, 1H); 7.41 (d, J=1.6 Hz, 1H). 7.52 (d, J=8.4 Hz, 1H). MS (ESI):m/z=372.3 (M+H⁺).

Example 714-((1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)butanamide 33b(Scheme 9)

Colorless oil (0.28 g, 58%). ¹HNMR (400 MHz, CDCl₃): δ 0.63-0.69 (m,1H); 0.81 (d, J=6.8 Hz, 3H); 0.86 (d, J=6.8 Hz, 3H); 1.05-1.08 (m, 1H);1.39 (t, J=7.2 Hz, 3H); 1.55-1.64 (m, 1H); 1.68-1.77 (m, 3H); 1.79-1.86(m, 1H); 2.08-2.15 (m, 1H); 2.43-2.33 (m, 5H); 2.68 (dd, J=2.4 Hz; 10.0Hz, 1H); 2.74-2.82 (m, 3H); 4.09 (q, J=7.2 Hz, 2H); 5.32 (sbroad, 1H);6.08 (sbroad, 1H); 6.82 (d, J=8.8 Hz, 2H); 7.12 (d, J=8.8 Hz, 2H). MS(ESI): m/z=347.3 (M+H⁺).

Example 72 General Procedure for 33c-33j

Trimethyl aluminium 2.0 M solution in toluene (3 eq) was added drop wiseto a stirred solution of compounds 13 (1 eq) and corresponding amines (6eq) in 10 mL of toluene under N₂ atmosphere at 0° C. in a sealed tube.The reaction mixture was slowly raised to 70° C. for 1 hour. After thereaction was completed, the mixture was distilled under vacuo to getafter silica gel chromatography4-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)-N-ethylbutanamideas colorless oil.

4-((1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amion)-N-methylbutanamide33c (Scheme 9)

Colorless oil (0.32 g, 66%). ¹HNMR (400 MHz, CDCl₃): δ 0.57-0.64 (m,1H); 0.82 (d, J=6.8 Hz, 3H); 0.87 (d, J=6.8 Hz, 3H); 1.01-1.05 (m, 1H);1.55-1.61 (m, 1H); 1.70-1.78 (m, 3H); 1.88-1.87 (m, 1H); 2.10-2.13 (m,1H); 2.18-2.28 (m, 4H); 2.33-2.372 (m, 1H); 2.67-2.73 (m, 2H); 2.77 (d,J=4.8 Hz, 3H); 2.79-2.82 (m, 1H); 5.64 (sbroad, 1H); 7.04 (dd, J=2.4 Hz;8.4 Hz, 1H); 7.29 (d, J=2.4 Hz, 1H); 7.33 (d, J=8.4 Hz, 1H). MS (ESI):m/z=386.3 (M+H⁺).

Example 734-((1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)-N-ethylbutanamide33d (Scheme 9)

Colorless oil (0.64 g, 66%). ¹HNMR (400 MHz, DMSO): δ 0.54-0.60 (m, 1H);0.78 (d, J=6.4 Hz, 3H); 0.83 (d, J=6.8 Hz, 3H); 0.87-0.95 (m, 1H); 0.98(t, J=7.2 Hz, 3H); 1.57-1.69 (m, 4H); 1.84-1.87 (m, 1H); 2.07-2.14 (m,3H); 2.18-2.22 (m, 1H); 2.33-2.37 (m, 1H); 2.60-2.69 (m, 3H); 3.00-3.07(m, 2H); 3.17 (d, J=5.2 Hz, 1H); 7.20 (d, J=8.4 Hz, 1H); 7.41 (s, 1H);7.52 (d, J=8.4 Hz, 1H). 7.71 (sbroad, 1H). MS (ESI): m/z=400.2 (M+H⁺).

Example 744-((1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)-N-propylbutanamide33e (Scheme 9)

Colorless oil (0.62 g, 67%). ¹HNMR (400 MHz, DMSO): δ 0.54-0.60 (m, 1H);0.77-0.84 (m, 8H); 0.88 (sbroad, 1H); 0.92-0.98 (m, 1H); 1.17 (t, J=7.2Hz, 1H); 1.33-1.40 (m, 2H); 1.57-1.69 (m, 4H); 1.83-1.85 (m, 1H);2.08-2.14 (m, 3H); 2.18-2.21 (m, 1H); 2.33-2.37 (m, 1H); 2.61-2.70 (m,3H); 2.98 (q, J=6.8 Hz, 2H); 7.19 (d, J=8.4 Hz, 1H); 7.40 (s, 1H); 7.51(d, J=8.4 Hz, 1H). 7.71 (t, J=4.8 Hz, 1H). MS (ESI): m/z=414.2 (M+H⁺).

Example 754-((1-(1-(3,4-Dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)-N-isopropylbutanamide33f (Scheme 9)

Colorless oil (0.72 g, 66%). ¹HNMR (400 MHz, DMSO): δ 0.57-0.59 (m, 1H);0.78 (d, J=6.8 Hz, 3H); 0.82 (d, J=6.8 Hz, 3H); 0.92-0.98 (m, 2H); 1.01(d, J=6.4 Hz, 6H); 1.60 (t, J=6.8 Hz, 3H); 1.66-1.67 (m, 1H); 1.76-1.80(m, 1H); 2.06 (t, J=7.6 Hz, 2H); 2.12-2.39 (m, 6H); 3.78-3.83 (m, 1H);7.19 (dd, J=1.6 Hz; 8.4 Hz, 1H); 7.40 (d, J=1.6 Hz, 1H). 7.52 (d, J=8.4Hz, 1H); 7.58 (d, J=7.2 Hz, 1H). MS (ESI): m/z=414.2 (M+H⁺).

Example 764-((1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)-N-methylbutanamide33g (Scheme 9)

Colorless oil (0.56 g, 65%). ¹HNMR (400 MHz, CDCl₃): δ 0.63-0.700 (m,1H); 0.81 (d, J=6.8 Hz, 3H); 0.85 (d, J=6.8 Hz, 3H); 1.05-1.11 (m, 1H);1.36 (t, J=7.2 Hz, 3H); 1.58-1.62 (m, 1H); 1.66-1.78 (m, 3H); 1.88-1.87(m, 1H); 2.11-2.13 (m, 1H); 2.22-2.33 (m, 5H); 2.65-2.75 (m, 6H); 4.01(q, J=7.2 Hz, 2H); 6.08 (sbroad, 1H); 6.82 (d, J=8.4 Hz, 2H); 7.11 (d,J=8.4 Hz, 2H). MS (ESI): m/z=361.3 (M+H⁺).

Example 774-((1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)-N-ethylbutanamide33h (Scheme 9)

Colorless oil (0.67 g, 66%). ¹HNMR (400 MHz, DMSO): δ 0.57-0.60 (m, 1H);0.64 (sbroad, 1H); 0.77 (d, J=6.8 Hz, 3H); 0.80 (d, J=6.8 Hz, 3H);0.92-1.00 (m, 4H); 1.31 (t, J=6.8 Hz, 3H); 1.57-1.66 (m, 4H); 1.76-1.80(m, 1H); 2.06-2.17 (m, 5H); 2.28-2.32 (m, 1H); 2.64-2.65 (m, 2H);3.00-3.07 (m, 2H); 3.98 (q, J=6.8 Hz, 2H); 6.83 (d, J=8.8 Hz, 2H); 7.13(d, J=8.8 Hz, 2H). 7.71 (sbroad, 1H). MS (ESI): m/z=375.2 (M+H⁺).

Example 784-((1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)-N-propylbutanamide33i (Scheme 9)

Colorless oil (0.74 g, 66%). ¹HNMR (400 MHz, DMSO): δ 0.54-0.60 (m, 1H);0.67 (sbroad, 1H); 0.76-0.84 (m, 8H); 0.92-0.98 (m, 1H); 1.29-1.40 (m,5H); 1.56-1.66 (m, 4H); 1.78-1.82 (m, 1H); 2.06-2.17 (m, 5H); 2.28-2.33(m, 1H); 2.58 (d, J=8.8 Hz, 1H); 2.66 (t, J=6.4 Hz, 2H); 2.97 (q, J=6.8Hz, 2H); 3.98 (q, J=6.8 Hz, 2H); 6.83 (d, J=8.4 Hz, 2H); 7.12 (d, J=8.4Hz, 2H). 7.71 (sbroad, 1H). MS (ESI): m/z=389.2 (M+H⁺).

Example 794-((1-(1-(4-Ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)-N-isopropylbutanamide33j (Scheme 9)

Colorless oil (0.64 g, 66%). ¹HNMR (400 MHz, DMSO): δ 0.57-0.60 (m, 1H);0.64 (sbroad, 1H); 0.77 (d, J=6.8 Hz, 3H); 0.80 (d, J=6.8 Hz, 3H);0.92-0.98 (m, 1H); 1.01 (d, J=6.4 Hz, 6H); 1.31 (t, J=6.8 Hz, 3H);1.56-1.64 (m, 4H); 1.76-1.80 (m, 1H); 2.05 (t, J=7.6 Hz, 2H); 2.14 (q,J=8.4 Hz, 3H); 2.30-2.32 (m, 1H); 2.64-2.66 (m, 2H); 3.78-3.81 (m, 1H);3.98 (q, J=7.2 Hz, 2H); 6.83 (d, J=8.4 Hz, 2H); 7.12 (d, J=8.4 Hz, 2H).7.58 (d, J=7.2 Hz, 1H). MS (ESI): m/z=389.2 (M+H⁺).

Example 80 General Procedure for Compounds 35

A solution of1-(1-(3,4-dichlorophenyl))cyclobutyl)-3-methylbutan-1-amine (0.32 g,0.0011 mol) and isopropyl (2-oxoethyl)carbonate (0.15 g, 0.0010 mol) inEthanol anhydrous (10 mL) was stirred for 15 hours at 50° C. After thereaction was complete, the reaction mixture was cooled down to 0° C. andNaBH₄ (0.3 g, 5.0 eq) was added. The reaction mixture was stirred for 6hours from 0° C. to rt, And then NaHCO₃ solution was added. The productwas extracted with ethyl acetate, dried over Na₂SO₄ and evaporated underreduced pressure to give(1-((1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylisopropyl carbonate which was purified by silica gel columnchromatography using gradient of hexane and ethyl acetate, isolated as acolorless oil.

2-((1-(1-(3,4-dichlorophenyl)cyclobutyl)-3-methylbutyl)amino)ethylisopropyl carbonate 35a (Scheme 10)

Colorless oil (0.23 g, 57%). ¹HNMR (400 MHz, CDCl₃): δ 0.60-0.67 (m,1H); 0.82 (d, J=6.8 Hz, 3H); 0.86 (d, J=6.8 Hz, 3H); 1.01-1.08 (m, 1H);1.28 (d, J=6.4 Hz, 6H); 1.56-1.63 (m, 2H); 1.73-1.78 (m, 1H); 1.84-1.90(m, 1H); 2.10-2.13 (m, 1H); 2.19-2.26 (m, 2H); 2.34-2.37 (m, 1H); 2.74(dd, J=2.4 Hz; 10 Hz, 1H); 2.91-2.97 (m, 1H); 3.03-3.09 (m, 1H);4.09-4.17 (m, 2H); 4.83-4.89 (m, 1H); 7.03 (dd, J=2 Hz; 8.4 Hz, 1H);7.28 (d, J=2 Hz, 1H); 7.32 (d, J=8.4 Hz, 1H). MS (ESI): m/z=417.3(M+H⁺).

Example 812-((1-(1-(4-ethoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethyl isopropylcarbonate 35b (Scheme 10)

Colorless oil (0.2 g, 56%). ¹HNMR (400 MHz, CDCl₃): δ 0.64-0.70 (m, 1H);0.81 (d, J=6.8 Hz, 3H); 0.85 (d, J=6.8 Hz, 3H); 1.03-1.14 (m, 1H); 1.28(d, J=6.4 Hz, 6H); 1.39 (t, J=6.8 Hz, 3H); 1.53-1.65 (m, 2H); 1.70-1.79(m, 1H); 1.80-1.89 (m, 1H); 2.08-2.15 (m, 1H); 2.23-2.37 (m, 3H); 2.69(dd, J=2.4 Hz; 10 Hz, 1H); 2.98 (t, J=5.6 Hz, 2H); 4.01 (q, J=6.8 Hz,2H); 4.12 (td, J=1.2 Hz; 6 Hz, 2H); 4.83-4.87 (m, 1H); 6.81 (d, J=8.8Hz, 2H); 7.12 (d, J=8.8 Hz, 2H). MS (ESI): m/z=392.3 (M+H⁺).

Example 822-((1-(1-(4-buthoxyphenyl)cyclobutyl)-3-methylbutyl)amino)ethyl ethylcarbonate 35c (Scheme 10)

Colorless oil (0.26 g, 55%). ¹HNMR (400 MHz, CDCl₃): δ 0.63-0.70 (m,1H); 0.81 (d, J=6.8 Hz, 3H); 0.85 (d, J=6.8 Hz, 3H); 0.97 (t, J=7.2 Hz,3H); 1.04-1.10 (m, 1H); 1.29 (t, J=7.2 Hz, 3H); 1.43-1.50 (m, 2H);1.60-1.62 (m, 1H); 1.71-1.78 (m, 3H); 1.82-1.85 (m, 1H); 2.10-2.13 (m,1H); 2.25-2.34 (m, 3H); 2.69 (dd, J=2.8 Hz; 10 Hz, 1H); 2.98 (t, J=5.6Hz, 2H); 3.93 (t, J=6.4 Hz, 2H); 4.11-4.20 (m, 4H); 6.81 (d, J=8.8 Hz,2H); 7.12 (d, J=8.8 Hz, 2H). MS (ESI): m/z=406.3 (M+H⁺).

Example 83 Ethyl(2-hydroxyethyl)carbonate 38a (Scheme 11)

To a stirred solution of isopropyl chloroformate (2 g, 0.016 mol.) in 10mL of DCM at 0° C. under nitrogen atmosphere was added pyridine (3.8 mL,0.048 mol) and then ethylene glycol (2.7 mL, 3 eq). The progress of thereaction was monitored by thin layer chromatography (TLC). Afterstirring for 15 hrs at room temperature. After removing the solventunder reduce pressure, the residue was purified by silica gel columnchromatography to give 2-hydroxyethyl isopropyl carbonate as a colorlessoil (0.5 g, 42% yield). ¹HNMR (400 MHz, CDCl₃): δ 1.22 (t, J=7.2 Hz,3H); 2.94 (sbroad, 1H); 3.78 (t, J=4.4 Hz, 2H); 4.18 (t, J=4.4 Hz, 2H);4.07 (q, J=7.2H, 2H).

Example 84 2-Hydroxyethyl isopropyl carbonate 38b (Scheme 11)

Colorless oil (0.50 g, 42%). ¹HNMR (400 MHz, CDCl₃): δ 1.24 (d, J=6.4Hz, 6H); 2.94 (sbroad, 1H); 3.78 (t, J=4.4 Hz, 2H); 4.18 (t, J=4.4 Hz,2H); 4.78-4.85 (m, 1H).

Example 85 General Procedure for Compounds 34

To an ice-cooled and stirred solution of 2-hydroxy isopropyl carbonate(1.06 g, 0.0071 mol) and triethylamine (2.0 mL, 2 eq) in DMSO (5 mL) wasadded portionwise a solution of SO₃.Py (2.3 g, 0.014 mol.) in DMSO (5mL), and the whole was stirred at room temperature for 1 h. The progressof the reaction was monitored by thin layer chromatography (TLC). Afterthe reaction was complete, the reaction mixture was poured intoice-water solution and extracted with ethyl acetate. The extracted waswashed successively with aqueous HCl (0.5N), NaHCO₃ solution and brine,dried over MgSO₄, and concentrated under reduce pressure. The residuewas purified by silica gel chromatography using gradient of hexane andethyl acetate, isopropyl (2-oxoethyl) carbonate isolated as a colorlessoil

Ethyl (2-oxoethyl)carbonate 34a (Scheme 11)

Colorless oil (0.54 g, 50%). ¹HNMR (400 MHz, CDCl₃): δ 1.22 (t, J=7.2Hz, 3H); 4.63 (d, J=0.8 Hz, 2H); 4.07 (q, J=7.2 Hz, 2H); 9.62 (s, 1H).

Example 86 Isopropyl (2-oxoethyl) carbonate 34b (Scheme 11)

Colorless oil (0.40 g, 38%). ¹HNMR (400 MHz, CDCl₃): δ 1.31 (d, J=6.4Hz, 6H); 4.63 (d, J=0.8 Hz, 2H); 4.86-4.91 (m, 1H); 9.62 (s, 1H).

Example 87 In Vitro Pharmacology Results

The monoamine transporters inhibitory activities of selected compoundscycloalkylmethylamine derivatives comprising Formula (I) are reportedherein. The compounds were evaluated using well established radioligandbinding assays protocols (Galli, A. et al., J. Exp. Biol. 1995, 198,2197-2212; Giros, B. et al., Trends Pharmcol. Sci. 1993, 14, 43-49; Gu,H. et al., J. Biol. Chem. 1994, 269(10), 7124-7130; Shearman, L. P. etal, Am. J. Physiol., 1998, 275 (6 Pt 1), C1621-1629; Wolf, W. A. et al.,J. Biol. Chem. 1992, 267(29), 20820-20825). The human recombinanttransporter proteins dopamine (DAT), norepinephrine (NET) and serotonin(SERT) were selected for the in vitro assays. The radioligand bindingassays were carried out at 11 different test concentrations 0.1 nm to 1μm.

The assays were carried out in duplicates and the quantitative data arereported as Ki in the TABLE 1.

TABLE 1 DAT NET SERT Compound Ki (nM) Ki (nM) Ki (nM) 12q 7.2 38.2 10.612u 80.4 2340 5.7 21a 38.4 13.4 1 21b 158.5 1924 2.0 31a 52.7 77.7 27.831b 251.4 4728 25 33a-Racemic 1.5 50.1 8.1 33a-(R)-Isomer 0.91 30.3 2.333a-(S)-Isomer 126.1 3415 299.7 33b-Racemic 471.6 >10,000 5.4933b-(R)-Isomer 130.3 6515 2.79 33b-(S)-Isomer 4026 1086 328.9

What is claimed is:
 1. A compound of structural Formula (I):

or pharmaceutically acceptable salt thereof, wherein: n is 1; SP is aspacer of alkylene; X is O, S, or NH; Z is O, S, NH; R¹ is H; R² is H,alkyl, substituted alkyl, hydroxyl, alkoxy, or halogen; R³ and R⁴ areindependently hydrogen, alkyl, or substituted alkyl; R⁵ is hydrogen,C₁₋₆ alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, orheteroaryl; optionally one of more hydrogens of R¹, R², R³, R⁴, or R⁵ issubstituted with ²H (deuterium); and “*” denotes a carbon capable ofbeing optically active.
 2. The method of claim 1, wherein X is O.
 3. Themethod of claim 1, wherein X is NH.
 4. The method of claim 1, wherein Zis O.
 5. The method of claim 1, wherein Z is NH.
 6. The method of claim1, wherein R² is halogen.
 7. The method of claim 1, wherein R² isalkoxy.
 8. The method of claim 1, wherein R³ is alkyl.
 9. The compoundof claim 8, wherein R³ is ethyl, n-propyl, iso-propyl, n-butyl, s-butyl,or t-butyl.
 10. The compound of claim 1, wherein R⁴ is hydrogen.
 11. Themethod of claim 1, wherein R⁵ is alkyl.
 12. The method of claim 1,wherein R⁵ is aryl.
 13. The compound of claim 1, wherein the carbondenoted with the * is in the R configuration.
 14. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier, excipient, or diluent.